Neurostimulation methods and systems

ABSTRACT

Some embodiments of the present invention provide stimulation systems and components for selective stimulation and/or neuromodulation of one or more dorsal root ganglia through implantation of an electrode on, in or around a dorsal root ganglia. Some other embodiments of the present invention provide methods for selective neurostimulation of one or more dorsal root ganglia as well as techniques for applying neurostimulation to the spinal cord. Still other embodiments of the present invention provide stimulation systems and components for selective stimulation and/or neuromodulation of one or more dorsal root ganglia through implantation of an electrode on, in or around a dorsal root ganglia in combination with a pharmacological agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.13/706,100, filed Dec. 5, 2012, titled “NEUROSTIMULATION METHODS ANDSYSTEMS,” Publication No. US-2013-0165991-A1, which is acontinuation-in-part of U.S. patent application Ser. No. 12/051,770,filed Mar. 19, 2008, titled “NEUROSTIMULATION SYSTEM,” now U.S. Pat. No.8,712,546, which is a continuation of U.S. patent application Ser. No.11/221,576, filed Sep. 7, 2005, titled “NEUROSTIMULATION SYSTEM,”Publication No. US-2006-0052836-A1, now abandoned, which claims thebenefit of U.S. Provisional Patent Application No. 60/608,357, filedSep. 8, 2004, titled “NEUROSTIMULATION SYSTEMS AND METHODS,” each ofwhich is incorporated herein by reference in its entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

FIELD

The present invention relates to neurostimulation methods and systemsthat enable more precise stimulation of the nervous system. Inparticular, embodiments of the present invention provide for thecontrolled stimulation of spinal and paraspinal nerve root ganglion. Inone embodiment, the ganglion is a dorsal root ganglion (DRG) and inanother embodiment the ganglion is part of the sympathetic nervoussystem.

BACKGROUND

Application of specific electrical energy to the spinal cord for thepurpose of managing pain has been actively practiced since the 1960s.While a precise understanding of the interaction between the appliedelectrical energy and the nervous tissue is not fully appreciated, it isknown that application of an electrical field to spinal nervous tissuecan effectively mask certain types of pain transmitted from regions ofthe body associated with the stimulated nervous tissue. Morespecifically, applying particularized electrical pulses to the spinalcord associated with regions of the body afflicted with chronic pain caninduce paresthesia, or a subjective sensation of numbness or tingling,in the afflicted bodily regions. This paresthesia can effectivelyinhibit the transmission of non-acute pain sensations to the brain.

Electrical energy, similar to that used to inhibit pain perception, mayalso be used to manage the symptoms of various motor disorders, forexample, tremor, dystonia, spasticity, and the like. Motor spinalnervous tissue, or nervous tissue from ventral nerve roots, transmitsmuscle/motor control signals. Sensory spinal nervous tissue, or nervoustissue from dorsal nerve roots, transmit pain signals. Correspondingdorsal and ventral nerve roots depart the spinal cord “separately”;however, immediately thereafter, the nervous tissue of the dorsal andventral nerve roots are mixed, or intertwined. Accordingly, electricalstimulation intended to manage/control one condition (for example, pain)often results in the inadvertent interference with nerve transmissionpathways in adjacent nervous tissue (for example, motor nerves).

As illustrated in FIG. 1, prior art spinal column or spinal cordstimulators (SCS) commonly deliver electrical energy to the spinal cordthrough an elongate paddle 5 or epidural electrode array containingelectrodes 6 positioned external to the spinal cord dura layer 32. Thespinal cord dura layer 32 surrounds the spinal cord 13 and is filledwith cerebral spinal fluid (CSF). The spinal cord 13 is a continuousbody and three spinal levels 14 of the spinal cord 13 are illustrated.For purposes of illustration, spinal levels 14 are sub-sections of thespinal cord 13 depicting that portion where the dorsal and ventral rootsjoin the spinal cord 13. The peripheral nerve 44 divides into the dorsalroot 42 and dorsal root ganglion 40 and the ventral nerve root 41 eachof which feed into the spinal cord 13. An ascending pathway 92 isillustrated between level 2 and level 1 and a descending pathway 94 isillustrated from level 2 to level 3. Spinal levels 14 can correspond tothe vertebral levels of the spine commonly used to describe thevertebral bodies of the spine. For simplicity, each level illustratesthe nerves of only one side and a normal anatomical configuration wouldhave similar nerves illustrated in the side of the spinal cord 13directly adjacent the paddle 5.

Typically, SCS are placed in the spinal epidural space. Conventional SCSsystems are described in numerous patents. Additional details of theplacement and use of SCS can be found, for example, in U.S. Pat. No.6,319,241 which is incorporated herein by reference in its entirety. Ingeneral, the paddle 5 is about 8 mm wide and from 24 to 60 mm longdepending upon how many spinal levels are stimulated. The illustratedelectrode paddle 5 is adapted to conventionally stimulate all threespinal levels 14. These exemplary levels 1, 2 and 3 could be anywherealong the spinal cord 13. Positioning a stimulation paddle 5 in thismanner results in the electrodes 6 spanning a plurality of nerves, herethe dorsal root ganglion 40, the ventral root 41 and peripheral nerve 41on multiple spinal levels.

Because the paddle 5 spans several levels the generated stimulationenergy 8 stimulates or is applied to more than one type of nerve tissueon more than one level. Moreover, these and other conventional,non-specific stimulation systems also apply stimulation energy to thespinal cord and to other neural tissue beyond the intended stimulationtargets. As used herein, non-specific stimulation refers to the factthat the stimulation energy is provided to all spinal levels includingthe nerves and the spinal cord generally and indiscriminately. Even ifthe epidural electrode is reduced in size to simply stimulate only onelevel, that electrode will apply stimulation energy indiscriminately toeverything (i.e., all nerve fibers and other tissues) within the rangeof the applied energy 8. Moreover, larger epidural electrode arrays mayalter cerebral spinal fluid (CSF) flow thus further altering localneural excitability states.

Another challenge confronting conventional neurostimulation systems isthat since epidural electrodes must apply energy across a wide varietyof tissues and fluids (i.e., CSF fluid amount varies along the spine asdoes pia matter thickness) the amount of stimulation energy needed toprovide the desired amount of neurostimulation is difficult to preciselycontrol. As such, increasing amounts of energy may be required to ensuresufficient stimulation energy reaches the desired stimulation area.However, as applied stimulation energy increases so too increases thelikelihood of deleterious damage or stimulation of surrounding tissue,structures or neural pathways.

To achieve stimulation the targeted tissue, the applied electricalenergy should be properly defined and undesired energy application tonon-targeted tissue be reduced or avoided. An improperly definedelectric field may not only be ineffective in controlling/managing thedesired condition(s) but may also inadvertently interfere with theproper neural pathways of adjacent spinal nervous tissue. Accordingly, aneed exists for stimulation methods and systems that enable more precisedelivery of stimulation energy.

SUMMARY OF THE DISCLOSURE

In one embodiment, there is provided a method of stimulating a dorsalroot ganglion by implanting an electrode in proximity to the dorsal rootganglion; and activating the electrode to stimulate a portion of thedorsal root ganglion, or activating the electrode to stimulatesubstantially only the dorsal root ganglion.

In another embodiment, there is provided a method of stimulating a nerveroot ganglion by implanting an electrode into the nerve root ganglion;and activating the electrode to stimulate the nerve root ganglion.

In another embodiment, there is provided, a method of stimulating thespinal cord by implanting an electrode into the spinal cord; andproviding stimulation energy to spinal cord fibers using the electrode.

In another embodiment, there is provided a method of modulating nervoustissue within a dorsal root ganglion by implanting an electrode within adorsal root ganglion; and providing electrical stimulation from theelectrode to stimulate neural tissue within the dorsal root ganglion.

In another embodiment, there is provided a method of modulating a neuralpathway in the sympathetic nervous system by stimulating a spinal dorsalroot ganglion upstream of at least one ganglion of the sympathetic nervechain to influence a condition associated with the at least one ganglionof the sympathetic nerve chain.

In yet another embodiment, there is provided a neurostimulation systemhaving an electrode adapted for stimulation of only a nerve rootganglion; a signal generator coupled to the electrode; and a controllerto control the output of the signal generator.

In yet another embodiment, there is provided a method of stimulating thespinal cord by piercing the spinal dura matter; and placing an electrodeinto contact with a portion of the intra-madullary of the spinal cord.

In yet another embodiment, there is a method of stimulating the nervoussystem by implanting an electrode such that when the electrode isactivated, the electrode stimulates only a nerve root ganglion.

In yet another embodiment, there is provided a method of stimulatingneural tissue to treat a condition including stimulating an electrodeimplanted to stimulate only a dorsal root ganglion on a spinal levelwherein the stimulation treats the condition.

In yet another embodiment, there is provided a stimulation component,comprising a proximal connector; a distal electrode configured to beimplanted within the body at a stimulation site; an electrical leadconnected to the proximal connector and the distal electrode; a strainrelief mechanism in proximity to the stimulation site; and a fixationelement adapted to reduce the amount of movement of the electrical leadproximal to a fixation point in an anatomical structure proximal to thestimulation site. In one aspect, an electrode maintains its positionusing a strain relief when the stimulation site is a dorsal rootganglion.

In another embodiment, there is provided a stimulation component,comprising a proximal connector; a distal electrode configured to beimplanted within the body at a stimulation site; an electrical leadconnected to the proximal connector and the distal electrode; a strainrelief mechanism in proximity to the stimulation site; and a fixationelement adapted to reduce the amount of movement of the electrical leadproximal to a fixation point in an anatomical structure proximal to thestimulation site. In one aspect, an electrode maintains its positionusing a fixation element when the stimulation site is a dorsal rootganglion.

In yet another embodiment, there is provided a neurostimulationcomponent, comprising a body having a distal end and a proximal end anda length selected to implant the body within a targeted neural tissue; atip on the distal end of the body adapted to anchor in proximity to thetargeted neural tissue; and an electrode structure positioned on thebody adapted to neurostimulate only the targeted neural tissue.

In yet another embodiment, there is provided a method ofneurostimulating targeted neural tissue, comprising implanting anelectrode in a position adapted to neurostimulate only targeted neuraltissue; and providing a controlled stimulation signal from a signalgenerator coupled to the electrode.

In one embodiment, a method of stimulating a dorsal root ganglion of apatient is provided, wherein the method includes implanting at least oneelectrode in proximity to the dorsal root and activating the at leastone electrode to selectively stimulate at least a portion of the dorsalroot ganglion to create paresthesia in an area of the patient's body. Insome instances, activating the at least one electrode to selectivelystimulate includes providing stimulation energy below a threshold forstimulating a ventral root associated with the dorsal root ganglion. Inanother other instances, activating the at least one electrode toselectively stimulate includes providing a stimulation energy thatstimulates sensory nerves without stimulating motor nerves. In stillanother instances, activating the at least one electrode to selectivelystimulate includes providing a stimulation energy which preferentiallystimulates myelinated fibers over unmyelinated fibers.

In some embodiments, intensity and/or distribution of the paresthesialacks clinically significant changes during movement of the patient. Forexample, movement of the patient can include movement of the patientfrom an upright position to a recumbant position or vice versa.Additionally or alternatively, movement of the patient can includeflexion, extension or rotation of a portion of a spine of the patient.It may be appreciated that the lack of clinically significant changesduring movement of the patient can be due to anchoring of the electrodein position by an anchor. Or, the lack of clinically significant changesduring movement of the patient can be achieved without the use of ananchor.

In one embodiment, a method of stimulating a dorsal root ganglion of apatient includes implanting at least one electrode in proximity to thedorsal root ganglion so that the at least one electrode maintains itsposition in proximity to the dorsal root ganglion throughout a bodyposition change of the patient and activating the at least one electrodeto selectively stimulate at least a portion of the dorsal root ganglion.

In some instances, activating the at least one electrode to selectivelystimulate can include providing stimulation energy below a threshold forstimulating a ventral root associated with the dorsal root ganglion. Inother instances, activating the at least one electrode to selectivelystimulate includes providing a stimulation energy that stimulatessensory nerves without stimulating motor nerves. In still otherinstances, activating the at least one electrode to selectivelystimulate includes providing a stimulation energy which preferentiallystimulates myelinated fibers over unmyelinated fibers. In someembodiments, the body position change of the patient includes moving toa recumbant position from an upright position or vice versa.Additionally or alternatively, the body position change of the patientcan include flexion, extension or rotation of a portion of a spine ofthe patient. Maintaining position of the at least one electrode canmaintain intensity of paresthesia. Likewise, maintaining position of theat least one electrode can maintain distribution of paresthesia. Thus,maintaining position of the at least one electrode can maintainintensity and distribution of paresthesia. In one embodiment, the atleast one electrode can maintain its position due to anchoring by ananchor. In still another embodiment, the at least one electrode canmaintain its position without the use of an anchor.

BRIEF DESCRIPTION OF THE DRAWINGS

A better understanding of the features and advantages of the variousembodiments of the present invention will be obtained by reference tothe following detailed description and the accompanying drawings ofwhich:

FIG. 1 illustrates a conventional epidural electrode array positionedexternal to and stimulating a portion of the spinal cord;

FIG. 2A illustrates an embodiment an electrode implanted into a spinaldorsal root ganglion;

FIG. 2B illustrates how selective stimulation techniques of FIG. 2A mayraise a response threshold;

FIG. 3A illustrates a stimulation system with an electrode embodiment ofthe present invention implanted into a dorsal root ganglion (DRG) of aspinal level;

FIG. 3B relates the spinal nerve roots to their respective vertebralspinal levels;

FIG. 3C illustrates the various dermatomes of the body related to theirrespective nerve roots in FIG. 3B;

FIG. 4A illustrates a single electrode, single level activation patternand FIG. 4B illustrates an exemplary corresponding dermatome to thestimulation pattern of FIG. 4A;

FIG. 5A illustrates a single electrode per level, two level activationpattern and FIG. 5B illustrates an exemplary corresponding dermatome tothe stimulation pattern of FIG. 5A;

FIG. 6A illustrates a two electrode, single level activation pattern andFIG. 6B illustrates an exemplary corresponding dermatome to thestimulation pattern of FIG. 6A;

FIG. 7A illustrates a single electrode level and a two electrode levelactivation pattern and FIG. 7B illustrates an exemplary correspondingdermatome to the stimulation pattern of FIG. 7A;

FIG. 8A is a section view of a spinal level with an electrode beingimplanted into a dorsal root ganglia and FIG. 8B is the view of FIG. 8Awith the delivery catheter being withdrawn and the electrode implantedinto the dorsal root ganglia;

FIG. 9A is a section view of a spinal level with an electrode beingimplanted into a dorsal root ganglia using an approach that crosses amedial line of the level of interest and FIG. 9B is an enlarged view ofthe DRG in FIG. 9A with an implanted electrode;

FIG. 10A is a section view of a spinal level with an electrode beingimplanted onto or in the nerve root epinurium using an approach thatcrosses a medial line of the level of interest and FIG. 10B is anenlarged view of the implanted electrode in FIG. 10A;

FIG. 11 is a illustrates an alternative DRG implantation technique usingan approach along the peripheral nerve;

FIG. 12A illustrates an implantation technique using an electrode andanchor design illustrated in FIG. 12B;

FIG. 12C illustrates an alternative anchoring technique using thesurrounding vertebral bone;

FIG. 13A illustrates the monopolar stimulation component embodimentillustrated in FIG. 13B implanted in a DRG;

FIG. 14A illustrates the bi-polar stimulation component embodimentillustrated in FIG. 14B implanted in a DRG;

FIG. 15A is a chart illustrating the relationship between impedance andelectrode surface area;

FIG. 15B is a chart illustrating representative electrode areas forstimulation components of several embodiments of the invention;

FIGS. 16-20 are various alternative electrode embodiments;

FIG. 20A illustrates an electrode adapted to pierce through and anchorto targeted neural tissue;

FIG. 20B illustrates a securing ring adapted for use with the electrodein FIG. 20A;

FIG. 20C illustrates a piercing electrode embodiment in position tostimulate a ganglion in the sympathetic chain;

FIG. 20D illustrates a piercing electrode embodiment in position tostimulate a dorsal root ganglion;

FIG. 21 illustrates a coated electrode implanted into a DRG;

FIG. 22 illustrates the position of the DRG upstream of various a numberof stimulation mechanisms;

FIG. 23A illustrates a combination stimulation and agent deliveryelectrode that provides the threshold adjustment illustrated in FIG.23B;

FIGS. 23C and 23D illustrate combined stimulation and pharmacologicalagent delivery electrodes and systems;

FIG. 24 is a table listing several exemplary pharmacological agents andtheir uses;

FIG. 25 is an illustration of Na⁺ and Ca²⁺ channel blocking targets tomitigate c-fiber activity;

FIG. 26 is a schematic drawing of an embodiment of a pulse generator;

FIG. 27 is a schematic drawing of an electrode connector embodiment;

FIG. 28 is an alternative single pulse generator stimulation systemembodiment;

FIG. 29 is an alternative embodiment of a multi-pulse generatorstimulation system with generators in a master-slave arrangement;

FIG. 30 is an embodiment of a stimulation system adapted to treatconditions in spinal levels C1-C3;

FIGS. 31A and 31B illustrate, respectively, the result of stimulationprovided by embodiments of the present invention to increasesub-threshold signals above a threshold level;

FIG. 32 is an illustration of the sympathetic nervous system;

FIG. 33 is an illustration of a portion of sympathetic nervous systemneuromodulated by an stimulation system embodiment of the presentinvention;

FIG. 34 is an illustration of embodiments of the present inventionimplanted for the direct stimulation of a single sympathetic nerveganglion and a single dorsal root ganglion on the same spinal level;

FIG. 35 is an illustration of an embodiment of the present inventionimplanted for the direct stimulation of the spinal cord;

FIG. 36 is an illustration of two embodiments of the present inventionimplanted for the direct stimulation of the spinal cord;

FIGS. 37A-37C illustrate sealing embodiments used when implantingelectrodes into the spinal cord; and

FIG. 38 summarizes numerous alternative embodiments of the stimulationsystem of the present invention as applied to different portions of thespine and dorsal root ganglion.

FIGS. 39A-39B illustrate, respectively, the paresthesia intensity scalesused by a patient to rate the intensity of paresthesia perceived fromstimulation energy applied while standing up and lying down.

FIG. 40 is an example of data compiled for a given patient comparingstimulation level (current amplitude) and paresthesia intensity whilethe patient is in a particular body position.

FIG. 41 is a bar graph illustrating compiled paresthesia intensity datafrom 22 patients.

FIG. 42 is a line graph illustrating the maintenance of paresthesiaintensity over time.

FIGS. 43A-B are body maps illustrating areas in the patient body withshaded areas to indicate where paresthesia is felt while in an uprightposition and in a supine position, respectively.

DETAILED DESCRIPTION

Embodiments of the present invention provide novel stimulation systemsand methods that enable direct and specific neurostimulation techniques.For example, there is provided a method of stimulating a nerve rootganglion comprising implanting an electrode into the nerve root ganglionand activating the electrode to stimulate the nerve root ganglion. Asdiscussed in greater detail below, the nerve root ganglion may be adorsal root ganglion in some embodiments while in other embodiments thenerve root ganglion may be a nerve root ganglion in the sympatheticnervous system or other ganglion or tissue. In some embodiments,implanting the electrode includes forming an opening in the epinurium ofthe root ganglion and passing the electrode through the opening and intothe interior space or interfascicular space of the ganglion.

In other embodiments, portions of an electrode body pass completelythrough a ganglion while maintaining an active electrode areaappropriately positioned to deliver stimulation energy to the ganglion.In still other embodiments of the microelectrodes and stimulationsystems of the invention, the size, shape and position of amicroelectrode and the stimulation pattern or algorithm is chosen tostimulated targeted neural tissue and exclude others. In otheradditional embodiments, the electrode stimulation energy is delivered tothe targeted neural tissue so that the energy dissipates or attenuatesbeyond the targeted tissue or region.

Once the electrode is in place on, in or adjacent the desired nerve rootganglion, the activating step proceeds by coupling a programmableelectrical signal to the electrode. In one embodiment, the amount ofstimulation energy provided into the nerve ganglion is sufficient toselectively stimulate neural tissue. In a specific embodiment, thestimulation energy provided only stimulates neural tissue within thetargeted DRG. Alternatively, the stimulation energy beyond the DRG isbelow a level sufficient to stimulate, modulate or influence nearbyneural tissue.

In an example where the electrode is implanted into a dorsal rootganglion, the stimulation level may be selected as one thatpreferentially activates myelinated, large diameter fibers (such as Aβand Aα fibers) over unmyelinated, small diameter fibers (such asc-fibers). In additional embodiments, the stimulation energy used toactivate an electrode to stimulate neural tissue remains at an energylevel below the level to used ablate, lesion or otherwise damage theneural tissue. For example, during a radiofrequency percutaneous partialrhizotomy, an electrode is placed into a dorsal root ganglia andactivated until a thermolesion is formed (i.e., at an electrode tiptemperature of about 67° C.) resulting in a partial and temporarysensory loss in the corresponding dermatome. In one embodiment, thestimulation energy levels applied to a DRG remain below the energylevels used during thermal ablation, RF ablation or other rhizotomyprocedures.

Tissue stimulation is mediated when current flow through the tissuereaches a threshold, which causes cells experiencing this current flowto depolarize. Current is generated when a voltage is supplied, forexample, between two electrodes with specific surface area. The currentdensity in the immediate vicinity of the stimulating electrode is animportant parameter. For example, a current of 1 mA flowing through a 1mm² area electrode has the same current density in its vicinity as 10 mAof current flowing through a 10 mm² area electrode, that is 1 mA/mm². Inthis example, cells close to the electrode surface experience the samestimulation current. The difference is that the larger electrode canstimulate a larger volume of cells and the smaller electrode canstimulate a smaller volume of cells in proportion to their surface area.

In many instances, the preferred effect is to stimulate or reversiblyblock nervous tissue. Use of the term “block” or “blockade” in thisapplication means disruption, modulation, and inhibition of nerveimpulse transmission. Abnormal regulation can result in an excitation ofthe pathways or a loss of inhibition of the pathways, with the netresult being an increased perception or response. Therapeutic measurescan be directed towards either blocking the transmission of signals orstimulating inhibitory feedback. Electrical stimulation permits suchstimulation of the target neural structures and, equally importantly,prevents the total destruction of the nervous system. Additionally,electrical stimulation parameters can be adjusted so that benefits aremaximized and side effects are minimized.

FIG. 2A illustrates an embodiment of a stimulation system 100 of thepresent invention in place with an electrode 115 implanted into a spinaldorsal root ganglion 40. For purposes of illustration, spinal level 14,a sub-section of the spinal cord 13, is used to depict where the dorsalroot 42 and ventral root 41 join the spinal cord 13, indicated by 42Hand 41H respectively. The peripheral nerve 44 divides into the dorsalroot 42 and dorsal root ganglion 40 and the ventral nerve root 41. Forsimplicity, the nerves of only one side are illustrated and a normalanatomical configuration would have similar nerves positioned on theother side. The spinal dura layer 32 surrounds the spinal cord 13 and isfilled with cerebral spinal fluid (CSF). For clarity, the spinal duralayer or dura mater 32 alone is used to represent the three spinalmeninges—the pia mater, the arachnoid mater and the dura mater—thatsurround and protect the spinal cord 13.

Note that the electrode 115 is implanted medial to the peripheral nerve44 after the nerve root splits into the ventral nerve 41 containing themotor nerves and the dorsal root 42 containing the sensory nerves. Theelectrode 115 is also implanted lateral of the dura layer 32. Theadvantageous placement of one or more electrode embodiments of thepresent invention enables selective stimulation of neural tissue, suchas a nerve root ganglion, without stimulation of surrounding neuraltissue. In this example, a dorsal root ganglion 40 is stimulated withlittle or imperceptible amounts of stimulation energy provided to themotor nerves within the ventral nerve root 44, portions of the spinalcord 13, spinal level 14, or the peripheral nerve 44. Embodiments of thepresent invention are particularly well suited for providing paincontrol since the sensory fibers running through the dorsal rootganglion 40 may be specifically targeted. Advantageously, embodiments ofthe present invention may neuromodulate one or more the dorsal rootganglia for pain control without influencing surrounding tissue.

The stimulation system 100 includes a pulse generator that providesstimulation energy in programmable patterns adapted for directstimulation of neural tissue using small area, high impedancemicroelectrodes. The level of stimulation provided is selected topreferentially stimulate the Aβ and Aα fibers 52 over the c-fibers 54.Stimulation energy levels used by embodiments of the present inventionutilize lower stimulation energy levels than conventional non-direct,non-specific stimulations systems because the electrode 115 isadvantageously placed on, in or about a dorsal root ganglion 40. Basedon conventional gate control theory, it is believed that by stimulatingof the faster transmitting Aβ and Aα fibers 52 by the stimulationmethods of the present invention, the signal 53 from the fibers 52 willrelease opiates at the junction of the dorsal root 42 and the spinalcord 13. This release raises the response threshold at that junction(elevated junction threshold 56). The later arriving c-fiber signal 55remains below the elevated junction threshold 56 and goes undetected.

Accordingly, some embodiments of the present invention provide selectivestimulation of the spinal cord, peripheral nervous system and/or one ormore dorsal root ganglia. As used herein in one embodiment, selectivestimulation means that the stimulation substantially only neuromodulatesor neurostimulates a nerve root ganglion. In one embodiment, selectivestimulation of a dorsal root ganglion leaves the motor nervesunstimulated or unmodulated. In addition, in other embodiments,selective stimulation can also mean that within the nerve sheath, theA-myelinated fibers are preferentially stimulated or neuromodulated ascompared to the c-unmyelinated fibers. As such, embodiments of thepresent invention advantageously utilize the fact that A-fibers carryneural impulses more rapidly (almost twice as fast) as c-fibers. Someembodiments of the present invention are adapted to provide stimulationlevels intended to preferentially stimulate A-fibers over c-fibers.

In additional embodiments, selective stimulation can also mean that theelectrode (including an electrode coated with or adapted to deliver apharmacological agent, e.g., FIGS. 21, 23A, C and D) is in intimatecontact with the tissue or other nervous system component that is thesubject of stimulation. This aspect recognizes our advantageous use ofelectrode placement. In specific illustrative embodiments discussedfurther below, one or more stimulation electrodes are placed (1) againstor in contact with the outer sheath of a nerve root ganglion; (2) withina nerve root ganglion; (3) within the root ganglion interfascicularspace; (4) in contact with a portion of the spinal cord; (5) in aposition that requires piercing of the epidural space, the dura, nerveroot epinurium or a portion of the spinal cord; (6) in contact with aportion of the sympathetic nervous system or (7) in contact with neuraltissue targeted for direct stimulation.

Moreover, selective stimulation or neuromodulation concepts describedherein may be applied in a number of different configurations.Unilateral (on or in one root ganglion on a level), bi-lateral (on or intwo root ganglion on the same level), unilevel (one or more rootganglion on the same level) or multi-level (at least one root ganglionis stimulated on each of two or more levels) or combinations of theabove including stimulation of a portion of the sympathetic nervoussystem and one or more dorsal root ganglia associated with the neuralactivity or transmission of that portion of the sympathetic nervoussystem. As such, embodiments of the present invention may be used tocreate a wide variety of stimulation control schemes, individually oroverlapping, to create and provide zones of treatment.

FIG. 3A illustrates an embodiment of a stimulation system 100 of thepresent invention with an electrode 115 implanted into a dorsal rootganglion (DRG) 40. The figure illustrates three representative spinallevels 14 (i.e., spinal levels 1-3) of the spinal cord 13. Theperipheral nerve 44 feeds into the dorsal root ganglion 40 and theventral nerve root 41 each of which feed into the spinal cord 13. Thedorsal horns 37, 36 are also indicated. For clarity, the dura 32 andcomplete spinal cord 13 are not illustrated but are present as describedelsewhere in this application and as occur in human anatomy. Theseexemplary levels 1, 2 and 3 could be anywhere along the spinal cord 13.For simplicity, each level illustrates the nerves of only one side.

Using level 2 as a reference, an ascending pathway 92 is illustratedbetween level 2 and level 1 and a descending pathway 94 is illustratedfrom level 2 to level 3. Application of stimulation energy or signals tothe DRG 40 in level 2 may be used to block signals progressing upstreamfrom level 2 towards the path/pathways 92. Moreover, modulation appliedto portions of level 2 but may also be used to effectively block theneuron paths/pathways from another level (here, alternatively usinglevels 1 and/or 3) from reaching the brain. As such, application ofstimulation to the level 2 DRG 40 using an embodiment of an apparatusand/or method of the present invention may advantageously provide aneffective block of intrasegment pain pathways as well. It is to beappreciated that while three continuous levels are illustrated, someembodiments of the present invention may be used to stimulate 2 or moreadjacent levels and still other embodiments may be used to stimulate 2or more non-adjacent levels, or combinations thereof.

FIG. 3B relates the spinal nerve roots to their respective vertebralspinal levels. The letter C designates nerves and vertebrae in thecervical levels. The letter T designates vertebrae and nerves in thethoracic levels. The letter L designates vertebrae and nerves in thelumbar levels. The letter S designates vertebrae and nerves in thesacral levels. FIG. 3C illustrates the various dermatomes of the bodyrelated to their respective nerve roots using the designations in FIG.3B.

FIGS. 4-7 illustrate one embodiment of a stimulation system activatedunder a variety of control conditions to provide different levels anddegrees of pain control. FIGS. 4A, 5A, 6A and 7A all illustrate thestimulation system in various degrees of activation. FIGS. 4B, 5B, 6Band 7B illustrate a correspondingly influenced dermatome.

FIGS. 4A, 5A, 6A and 7A illustrate a stimulation system 100 having 3electrodes 115 implanted into dorsal root ganglia 40 on two adjacentspinal levels. For simplicity, each spinal level illustrates a dorsalroot ganglion 40, a ventral root 41 and a peripheral nerve 44. Theexception is spinal level 3 that illustrates an additional dorsal rootganglion 38, a ventral root 39 and a peripheral nerve 42. The threeelectrodes 115 are designated channels 1, 2 and 3 by the controller 106.Each electrode is activated to provide modulation energy or signalsunder the control of the controller 106. Exemplary electrodes forimplantation into a nerve root ganglion are further described withregard to FIGS. 12A-13B. Level 3 is an example of bilateral electrodeplacement and level 2 is an example of unilateral electrode placement.As such, the illustrated embodiment is a multi-level, unilateral andbi-lateral stimulation system. Stimulation energy is provided by a pulsegenerator (not illustrated but described in greater detail below inFIGS. 26-29) under control of a suitable neurostimulation controller106. Those of ordinary skill will recognize that any of a wide varietyof known neurostimulation controllers may be used. Not illustrated inthis view but present in the system are suitable connections between thevarious electrodes 115, electrode leads 110 and the controller 106. Inthe illustrations that follow, a line connecting the electrode lead 110to the controller 106 indicates “stimulation on” communication from thecontroller 106 to one electrode 115 (see FIG. 4A) or more than oneelectrode 115 (see FIG. 5A).

A signal of “stimulation on” indicates any of a wide variety ofstimulation patterns and degrees of stimulation. The “stimulation on”signal may be an oscillating electrical signal may be appliedcontinuously or intermittently. Furthermore, if an electrode isimplanted directly into or adjacent to more than one ganglion, theoscillating electrical signal may be applied to one electrode and notthe other and vice versa. One can adjust the stimulating poles, thepulse width, the amplitude, as well as the frequency of stimulation andother controllable electrical and signally factors to achieve a desiredmodulation or stimulation outcome.

The application of the oscillating electrical signal stimulates the areaof the nerve chain where the electrode 115 is placed. This stimulationmay either increase or decrease nerve activity. The frequency of thisoscillating electrical signal is then adjusted until the symptomsmanifest by physiological disorder being treated has been demonstrablyalleviated. This may step may be performed using patient feedback,sensors or other physiological parameter or indication. Once identified,this frequency is then considered the ideal frequency. Once the idealfrequency has been determined, the oscillating electrical signal ismaintained at this ideal frequency by storing that frequency in thecontroller.

In one specific example, the oscillating electrical signal is operatedat a voltage between about 0.5 V to about 20 V or more. More preferably,the oscillating electrical signal is operated at a voltage between about1 V to about 30 V or even 40V. For micro stimulation, it is preferableto stimulate within the range of 1V to about 20V, the range beingdependent on factors such as the surface area of the electrode.Preferably, the electric signal source is operated at a frequency rangebetween about 10 Hz to about 1000 Hz. More preferably, the electricsignal source is operated at a frequency range between about 30 Hz toabout 500 Hz. Preferably, the pulse width of the oscillating electricalsignal is between about 25 microseconds to about 500 microseconds. Morepreferably, the pulse width of the oscillating electrical signal isbetween about 50 microseconds to about 300 microseconds.

The application of the oscillating electrical signal may be provided ina number of different ways including, but not limited to: (1) amonopolar stimulation electrode and a large area non-stimulatingelectrode return electrode; (2) several monopolar stimulating electrodesand a single large area non-stimulating return electrode; (3) a pair ofclosely spaced bi-polar electrodes; and (4) several pairs of closelyspaced bi-polar electrodes. Other configurations are possible. Forexample, the stimulation electrode(s) of the present invention may beused in conjunction with another non-stimulating electrode—the returnelectrode—or a portion of the stimulation system may be adapted and/orconfigured to provide the functionality of a return electrode. Portionsof the stimulation system that may be adapted and/or configured toprovide the functionality of the return electrode include, withoutlimitation, the battery casing or the pulse generator casing.

In the illustrated configuration, a stimulation pattern provided to oneof the electrodes positioned in level 3 (i.e., channel #1 “ON”) producespain blocking/relief in the indicated region of the body (i.e., shadedarea R1) in FIG. 4B.

It will be appreciated that embodiments of the present invention canstimulate specific dermatome distributions to probe which electrode orgroup of electrodes or combination of electrodes (including drug coatedor delivery electrodes) is best positioned or correlates most closely toone or more specific areas of pain. As such, a stimulation systemaccording to an embodiment of the present invention may be “fine tuned”to a specific area of coverage or type of pain. The results obtainedfrom such testing can be used to one or more stimulation or treatmentregimes (i.e., series of stimulations in the presence of or incombination with a therapeutic agent from a coated electrode) for aparticular patent for a particular type of pain. These pain treatmentregimes may be programmed into a suitable electronic controller orcomputer controller system (described below) to store the treatmentprogram, control and monitor the system components execution of thestimulation regime as the desired therapeutic regime is executed.

FIG. 5A provides another example of distribution of pain relief using amulti-channel stimulation system and method. In the illustratedconfiguration and stimulation pattern, a stimulation pattern is providedto one electrode each in levels 2 and 3 via channels #1 and #2. Thisstimulation electrode pattern provides pain blocking/relief in theindicated region of the body (i.e., areas R1, R2) of FIG. 5B.

FIG. 6A provides another example of distribution of pain relief using amulti-channel stimulation system and method. In the illustratedconfiguration and stimulation pattern, a stimulation pattern provided toboth electrodes in level 3 via channels #1 and #3 provides painblocking/relief in the indicated region of the body (i.e., area R3) ofFIG. 6B.

FIG. 7A provides another example of distribution of pain relief using amulti-channel stimulation system and method. In the illustratedconfiguration and stimulation pattern, a stimulation pattern is providedto all electrodes in the system via channels #1, #2 and #3. Thisstimulation electrode pattern provides pain blocking/relief in theindicated region R4 of the body (i.e., FIG. 7B). It is to be appreciatedthat the electrode placement and blocking region patterns illustrated byFIGS. 4A-7B may be modified using information such as in FIGS. 3B and 3Cfor targeted placement to specific portions of the body depending uponindividual needs.

Micro-electrode and stimulation system embodiments of the presentinvention may be implanted into a single nerve root ganglion utilizingthe implantation methods of the present invention. The implantationmethods described herein provide numerous advantages, including but notlimited to: low risk percutaneous access route similar to otherprocedures, direct delivery of localized quantities of pharmacologicalagents at the nerve root when using embodiment having electrodes coatedwith pharmacological agents, and electrode placement that enablespreferential, selective nerve fiber stimulation.

FIG. 8A illustrates a cross section view of a spinal level. Peripheralnerves 44, 42 feed into dorsal root ganglia 40, 38 and ventral nerves41, 39 respectively. A vertebral body 70 and two sympathetic nerveganglia 62, 63 are also illustrated. In this embodiment, the methodincludes advancing a suitable catheter 107 medially towards thevertebral body 70, then along the peripheral nerve 42 towards the dorsalroot ganglion 38. The catheter 107 is advanced using external imagingmodalities for guidance such as fluoroscopy or other suitable medicalimaging technique. The vertebral foramen offers a good landmark visibleunder fluoroscopy and useful in locating the DRG 38.

The electrode 115 is implanted in proximity to the dorsal root ganglionby forming an opening in the dorsal root ganglion epinurium and passingthe electrode through the opening (FIG. 8A, 8B). The opening may beformed using conventional methods such as a cutting edge on or providedto the tip of the catheter 107, with an instrument advanced through aworking channel within the catheter 107 or through the use of othersuitable endoscopic or minimally invasive surgical procedure.Alternatively, the electrode body or distal end may be provided with atissue cutting or piercing element to aid in piercing tissue (see, e.g.,tip 908 in FIG. 20A). As the catheter 107 is withdrawn, themicroelectrode leads 110 are deployed and attached, anchored orotherwise secured to the tissue, anatomy or bones adjacent the DRG 38 toreduce the likelihood that electrode 115 will be pulled from the DRG 38.In alternative embodiments described below, the microelectrode leads 110may be fixed prior to electrode implantation into a nerve root ganglion.

Note that the electrode 115 is sized and shaped to fit within the DRG38. A typical DRG is generally spherical with a diameter of 3-5 mm. Ofcourse, a range of DRG sizes occur in humans and may vary in sizedepending on the age and sex of the individual and other factors.Electrode embodiments may be provided in a range of sizes to accommodatethe specific anatomical characteristics of a patient. A number offactors are considered when selecting an appropriate DRG electrodeembodiment for use in an individual.

Electrode placement within the DRG may be confirmed usingneurodiagnostic testing techniques such as somatosensory evokedpotential (SSEP) and electromyography (EMG) adapted for the methods andsystems described herein. One illustrative example includes theplacement of sensing electrodes in the sensory nervous system above andbelow the DRG level having the implanted electrode(s). Implant theelectrode into the targeted DRG. Apply a test stimulation to the DRG andmeasure voltage potential at the sensory electrodes above and below thetargeted DRG to confirm that the electrode is implanted in the targetedDRG. A test stimulation may range from 0.4 v to 0.8 v at 50 Hz or may besome other suitable stimulation level based on the evoked potentialmeasurement technique used. In this way, conventional fluoroscopytechniques and instruments may be used to advance towards and implantthe electrode into the DRG and confirm that the electrode is correctlyimplanted and stimulating the targeted DRG.

A number of different approaches are available for maneuvering anelectrode into position on, in or about a DRG. Several exemplaryapproaches are provided in FIGS. 8-10 in a section view of the caudaequina portion of the spinal cord. In these examples, electrodes 115 areplaced on or in a ganglion on a representative sacral spinal level.Sympathetic nervous system ganglia 62, 63 are also indicated. DRG 40 andventral root 41 are associated with peripheral nerve 44. DRG 38 andventral root 39 are associated with peripheral nerve 42.

FIGS. 8A and 8B illustrate a lateral approach to a DRG 38 using asuitable catheter 107. The catheter advances adjacent to the peripheralnerve 42 medially towards the DRG 38. The DRG dura is pierced laterallyand the electrode 115 is advanced into the DRG interior. Thereafter, theelectrode 115 is implanted into the DRG interior. Next, as isillustrated in FIG. 8B, the catheter 107 is withdrawn from the DRG 38and deploys the electrode leads 110. The electrode leads 110 may beanchored to the vertebral body 70 using suitable fixation techniques.The leads 110 are then connected to a pulse generator/controller (notshown).

FIG. 9A is anatomically similar to FIGS. 8A and 8B. FIG. 9A illustratesan alternative DRG implantation approach that crosses the medial lineinferior to the DRG of interest. The catheter 107 is advanced in asuperior pathway towards the foramen and using the foramen underfluoroscopic guidance into the DRG. As illustrated in FIGS. 9A and 9B,there is provided a method of stimulating a dorsal root ganglion byimplanting an electrode within the dorsal root ganglion. In someembodiments, the implanting procedure includes passing a portion of theelectrode through the spinal epidural space. Electrodes in systems ofthe present invention onto or in the nerve root epinurium 72 (FIGS. 10Aand 10B) or within the nerve root (i.e., FIGS. 9A,B). Moreover, in someembodiments, there is also the step of forming an opening in the dorsalroot ganglion epinurium 72 and then passing the electrode through theopening (see, i.e., FIG. 9B).

FIG. 11 illustrates a section view through a portion of the spinal cord13 with another alternative electrode implantation technique. Incontrast to the earlier described methods that externally approach theDRG and involve piercing or entering the DRG epinurium 72, FIG. 11illustrates an internal approach to the DRG interlascular from withinthe nerve sheath of a peripheral nerve 44. FIG. 11 illustrates a sectionview of the nerve sheath partially removed to reveal the underlyingnerve bundle 46. In this illustrative example, an opening is made in theperipheral nerve 44 sheath at a point 45 lateral to the DRG 40. Themicroelectrode 115 enters the nerve 44 sheath through opening 45 usingsuitable endoscopic or minimally invasive surgical techniques. Next, theelectrode 115 is advanced towards and into the DRG 40.

As each of these illustrative embodiments make clear, the placement ofthe electrode relative to the DRG enables activating the electrode toselectively stimulate sensory nerves. Additionally, the placement of theelectrode according to the methods of the invention enable activatingthe electrode to stimulate sensory nerves within the DRG or withoutstimulating motor nerves in the nearby ventral root. The control systemdescribed herein also provides stimulation levels that activate theelectrode to stimulate at a level that preferably stimulates myelinatedfibers over unmyelinated fibers.

In addition, as will be described in greater detail below, FIG. 11illustrates an electrode embodiment where the electrode tip and shaftmay be coated with pharmacological agents to assist in the stimulationtherapy or provide other therapeutic benefit. As illustrated, theelectrode includes a tip coating 130 and a shaft coating 132. Thepharmacological agent in each coating 130, 132 could be the same ordifferent. One advantage of implanting through the nerve sheath is thatthe coated shaft 132 may include a pharmacological agent active orbeneficial to neural activity in the ventral nerve root 41 since thiscoated shaft is advantageously positioned proximal to the ventral root41. The shaft coating 132 may also be selected to reduce inflammation orirritation caused by the presence of the shaft within the nerve sheath.

FIGS. 12A and 12B illustrate an embodiment of an exemplary anchor body171 with a fixation hook 172 used to secure the leads 110 once theelectrode 115 is implanted into the DRG 40. FIG. 12A is a section viewof a portion of the spinal cord 13 showing the dorsal root 42, ventralroot 41, DRG 40 and peripheral nerve 44. In this illustrativeembodiment, a catheter 107 is used to maneuver the electrode 115, leads110 and anchor 171 about the DRG 40 implantation site. Once a suitablesite is identified, the hook 172 is inserted into the fascia layer ofthe DRG. The hook 172 may have various shapes and contours to adapt itto engaging with and securing to the outer DRG layer or within the outerDRG layer. FIG. 12B illustrates an exemplary anchor body 171 and hook172 mounted onto the distal end of a catheter 107. The anchor body 171and hook 172 may be maneuvered into position using the catheter 107alone or in combination with other suitable surgical, endoscopic orminimally invasive tools. Similarly, the electrode 115, leads 110 may bemoved into position for implantation on, in or about targeted neuraltissue. In other alternative electrode embodiments, the electrode 115 isimplanted on, in or about a DRG is provided with a flexible tip thathelps to prevent or mitigate chronic friction and ulceration.

Alternatively, the electrode leads 110 or other supporting or anchoringstructures may be attached to the adjacent bony structure, soft tissueor other neighboring anatomical structures. In addition, there may alsobe provided a fixation, anchoring or bonding structure positionedproximal to the electrode anchor 172 that absorbs some or all proximalmovement of the leads 110 so that the electrode is less likely to bepulled from or dislodged from the implantation site. The goal of theanchoring and other strain absorbing features is to ensure the electroderemains in place within or is less likely to migrate from the implantedposition because of electrode lead 110 movement (i.e., lead 110 movementpulls the electrode 115 from the implantation site or disrupts theposition of the electrode 115 within the implantation site). It is to beappreciated that numerous techniques are available to aid in electrodeplacement including percutaneous placement of single/multiple hooks oranchors, vertebral anchor or posts, micro-sutures, cements, bonds andother joining or anchoring techniques known to those of ordinary skillin the art. It is also to be appreciated that other components of thestimulation system embodiments described herein may also be adapted forattachment to surrounding tissue in proximity to the stimulation site ornear the electrode implantation site. Other components include, forexample, the stimulation controller, master controller, slavecontroller, pulse generator, pharmacological agent reservoir,pharmacological agent pump and the battery.

FIG. 12C illustrates an exemplary anchoring of electrode leads 110 tobone surrounding the electrode implantation site. FIG. 12C illustrates asection view through a portion of the spinal cord 13 showing the ventralroot 41, the dorsal root 42 and dorsal root ganglion 40. FIG. 12C alsoillustrates the surrounding bone of the spine such as vertebral body1110, the spinous process 1115, the pedicle 1120, the lamina 1125, thevertebral arch 1130, transverse process 1135, and facet 1140. Electrode115 is implanted into the DRG 40 and the electrode leads are held inplace using a suitable anchor 111. In this embodiment, the anchor 111 issecured to the vertebral body 1110. The anchor 111 represents anysuitable manner of securing the bony portions of the spine such astacks, staples, nails, cement, or other fixation methods known to thosein the surgical or orthopedics arts. A strain relief 122 is presentbetween anchor 111 and the DRG 40 (see FIGS. 13A and 14A). The strainrelief 122 is used to absorb motion that may move the electrode 115within the DRG 40 or remove the electrode from the DRG 40. In thisillustrative embodiment, the strain relief 122 is a coiled portion ofthe electrode lead 110. One or more strain reliefs 122 may be providedbetween the anchor 111 and the DRG 40 or between the anchor 111 and thebattery or controller of the stimulation system (not shown).

FIGS. 13A-14B illustrate mono-polar and bi-polar stimulation componentembodiments of the present invention. FIG. 13A illustrates a mono-polarstimulation component that has a proximal connector 126A adapted to beconnected to a pulse generator. A distal electrode 115 is configured tobe implanted within the body at a stimulation site. The distal electrodemay be a mono-polar electrode 115A (FIG. 13B) or a bi-polar electrode115B (FIG. 14B). The electrodes are sized for implantation into a nerveroot ganglion and will vary according to the nerve root selected. Inadditional alternative embodiments, the electrode leads and electrodeare adapted and sized to advance within a nerve sheath to a nerve rootganglion. The electrodes or their casing may be made of inert material(silicon, metal or plastic) to reduce the risk (chance) of triggering animmune response. Electrodes should be studied for suitability to MRI andother scanning techniques, including fabrication using radio-opaquematerials as described herein.

Returning to FIG. 13A, an electrical lead 110 is connected to theproximal connector 126A and the distal electrode 115. A strain reliefmechanism 122 is connected in proximity to the stimulation site. Theillustrated strain relief mechanism is formed by coiling the electricallead 110. Other well known strain relief techniques and devices may beused. A fixation element 124 adapted to reduce the amount of movement ofthe electrical lead proximal to a fixation point is positioned in, on,or through an anatomical structure proximal to the stimulation site.Multiple elements are provided to mitigate or minimize strain and forcetransmission to the micro-leads 110 or the microelectrodes 115 becausethe microelectrodes and microelectrode leads used herein are very smalland include fine, flexible wires on the order of 1 mm or less and inmany cases less than 0.5 mm. Representative electrode and leaddimensions will be described in greater detail below (FIG. 15A, 15B). Assuch, in some embodiments, strain and movement may be absorbed ormitigated by the fixation element 124, the strain relief 122 and theelectrode anchor 117 (if included). The fixation element 124 may be, forexample, a loop, or a molded eyelet. The fixation element may besutured, tacked, screwed, stapled, bonded using adhesives or joinedusing other techniques known to those of ordinary skill to secure thefixation element within the body for the purposes described herein.

In one specific implantation embodiment, the method of implanting theelectrode is modified based on consideration of the small size anddelicate nature of the microelectrode and microelectrode leads. As such,high force actions are taken first followed by light force actions. Inthis way, the fine microelectrode and microelectrode lead materials arenot present during high force operations. Consider an example where anelectrode of the present invention will be implanted into a DRG. In anexemplary embodiment, the fixation element 124 is a loop sized to allowpassage of the electrode 115. Perform the high force operation ofanchoring or otherwise fixing (i.e., adhesion) the fixation element intoa vertebral foramen adjacent the selected DRG stimulation site. Ingeneral, the fixation site should be as close as practical to thestimulation site. In one specific embodiment, the fixation site iswithin 3 cm to 5 cm of the stimulation site. Optionally, a guide wireattached to the loop remains in place and is used to guide the electrodeand leads to the loop and hence to the implant site. The electrode andleads are passed through the loop (with or without use of a guide wire).The electrode is then implanted on or in the DRG. Optionally, ananti-strain device 122 may also be positioned between the electrode inthe implantation site and the fixation element 124. In one illustrativeembodiment, a section of microelectrode lead containing a plurality ofloops is used as an anti-strain device 122. Finally, the microelectrodelead is secured to the loop using a suitable locking device. It is to beappreciated that the above method is only illustrative of one method andthat the steps described above may be performed in a different order ormodified depending upon the specific implantation procedure utilized.

In some embodiments, there may also be provided an anchoring mechanismproximal to the distal electrode 115. Examples of anchoring mechanismsinclude, for example, anchors 117 illustrated in FIGS. 13B and 14B. Instill further embodiments, the anchoring mechanism is adapted to anchorthe distal electrode 115 within the stimulation site. For example, theanchor mechanism may remain stowed flat against the electrode body 118during implantation and then deploy from within a nerve root ganglion toanchor against the interior nerve root wall to support the electrode andprevent electrode migration or pull-out. In some embodiments theanchoring mechanism and the distal electrode are integrally formed andin other embodiments they are separate components. In some embodiments,the anchoring mechanism is formed from a polymer or a silicone.

Selective nerve stimulation affords the use of smaller electrodes.Smaller electrodes create less impingement and are less susceptible tounwanted migration. However, as electrode surface area decreases theimpedance of the electrode increases (FIG. 15A). As such, some electrodeembodiments will have an impedance much greater than the impedance ofconventional stimulation electrodes. In one embodiment, the impedance ofa microelectrode of the present invention is more than 2500Ω. Thisdifference in impedance also impacts the performance requirements ofstimulation systems, pulse generators and the like used to drive themicroelectrodes described herein.

Distal electrodes may come in a wide variety of configurations, shapesand sizes adapted for implantation into and direct stimulation of nerveroot ganglion. For example, the distal electrode 115 may be a ring ofconductive material attached the leads 110. Alternatively, the distalelectrode 115 may be formed from an un-insulated loop of electricallead. The loop electrode is appealing and has improved wear propertiesbecause, unlike the ring that must be joined to the leads 110, the loopis formed from the lead and no joining is needed. In still otherembodiments, the electrode may be an un-insulated portion of the lead.

Regardless of configuration, electrodes of the present invention aresized and adapted for implantation into, on or about a ganglion such as,for example, a dorsal root ganglion or a ganglion of the sympatheticnervous system. It is to be appreciated that the size of the electrodevaries depending upon the implantation technique and the size of thetarget ganglion. An electrode implanted through the DRG dura (i.e., FIG.9A) may be less than 5 mm since the diameter of a DRG may be only 3-5mm. On the other hand an electrode adapted for implantation along theperipheral nerve sheath (i.e., FIG. 11) may be longer than the electrodethat passes through the dura but may face other design constraints sinceit must advance distally within the nerve sheath to reach the DRG. It isto be appreciated that dimensions of electrode embodiments of thepresent invention will be modified based on, for example, the anatomicaldimensions of the implantation site as well as the dimensions of theimplantation site based on implantation method.

FIG. 15B provides some exemplary electrode surface areas for electrodeembodiments formed from wire diameters between 0.25 mm to 1 mm, havingwidths of 0.25 mm or 0.5 mm. As such, embodiments of the presentinvention provide distal electrode surface area that is less than 0.5mm². In other embodiments, the distal electrode surface area is lessthan 1 mm². In still other embodiments, the distal electrode surfacearea is less than 3 mm².

The sizes of the electrodes of the present invention stand in contrastto the conventional paddle 5 having dimensions of about 8 mm wide andfrom 24 to 60 mm long (FIG. 1). One result is that conventionalstimulation electrodes have larger electrode surface areas thanelectrode embodiments of the present invention. It is believed thatconventional electrodes have an impedance on the order of 500 to 1800Ωoperated using a stimulation signal generated by a 10-12 volt pulsegenerator. In contrast, stimulation electrode embodiments of the presentinvention have an impedance on the order of 2 kΩ or about 2500Ω, from 2kΩ to 10 kΩ or higher or even in the range of 10 kΩ to 20 kΩ. As will bedescribed in greater detail below, some pulse generator embodiments ofthe present invention operate with voltages produced by DC-DC conversioninto ranges beyond conventional stimulation systems.

The electrodes may be formed from materials that are flexible and havegood fatigue properties for long term use without material failure. Theelectrode material should be formed from a biocompatible material orcoated or otherwise treated to improve biocompatibility. Additionally,electrode materials should be opaque to imaging systems, such asfluoroscopy, used to aid electrode placement during implantationprocedures. Examples of suitable materials include but are not limitedto Pt, Au, NiTi, PtIr and alloys and combinations thereof. Electrodesmay also be coated with a steroid eluding coating to reduce inflammationat the implantation or stimulation site.

With the small surface areas, the total energy required for stimulationof the DRG is drastically reduced because we can achieve high currentdensities with low currents. One advantage of using microelectrodes isthat only a small volume of tissues in the immediate vicinity of theelectrodes is stimulated. Another advantage of using microelectrodes isthe correspondingly smaller pulse generator and because of decreasedbattery size.

In addition to the implantable electrodes described above, alternativeelectrode embodiments may also be used to selectively stimulate a nerveroot ganglion. FIG. 16 illustrates an embodiment where conductive rings205, 207 are positioned on either end of a dorsal root ganglion 40. Whenactivated, the rings 205, 207 capacitively couple stimulation energyinto the DRG 40. FIG. 17 illustrates an alternative capacitivestimulation configuration where the capacitive plates 210, 212 areattached to the DRG dura. Embodiments of the present invention are notlimited to only one pair of capacitive plates but more than one pair maybe used. FIG. 18 illustrates two pairs of capacitive plates attached tothe dura of a DRG 40. One pair includes plates 210, 212 and the otherpair includes plate 214 and another plate (not shown). As an alternativeto attaching the plates directly to the dura, the plates may be attachedto an electrode support element 230 adapted to slip around and engagewith the DRG dura. Once the electrode support element 230 is in positionabout the DRG, the plates are properly positioned to selectivelystimulate a DRG. The present invention is not limited to onlycapacitively coupled stimulation energy. FIG. 20 illustrates anotheralternative embodiment where a wire 235 is wrapped around a DRG 40creating coils 236 that may be used to inductively couple stimulationenergy into a nerve root ganglion. For purposes of discussion, theseembodiments have been described in the context of stimulation a DRG. Itis to be appreciated that the techniques and structures described hereinmay also be used to stimulate other nerve root ganglion, other neuralstructures or other anatomical features.

FIGS. 20A and 20B illustrate another electrode embodiment adapted forimplantation through neural tissue. Piercing electrode 900 has a body902, a distal end 904, and a proximal end 906. An electrode surface orcomponent 912 receives stimulation signals and energy from a pulsegenerator/controller (not shown) via a suitable lead 914. The distal and904 has a tip 908 adapted to pierce the targeted neural tissue. Inaddition, one or more anchors 910 are provided at the distal end to helpsecure the electrode body 902 within the targeted neural tissue. Asecuring ring 920 (FIG. 20B) is provided to secure the electrode body902 to or relative to the targeted neural tissue. The anchors 910 may bein a first or stowed position against the electrode body 902 duringinsertion through the neural tissue and then be moveable into a secondor deployed position away from the electrode body 902. In the deployedposition (FIGS. 20A, 20C and 20D) the anchors 910 resist the movement ofthe electrode 900 out of the neural tissue. Numerous alternative anchorconfigurations are possible. Anchor 910 could be a series of individualstruts arrayed in a circular pattern or struts with material betweenthem similar to the construction of an umbrella. Anchor 910 could alsobe a single anchor.

The electrode 900 includes a body 902 adapted to pass completely throughtargeted neural tissue while positioning the electrode 912 within aportion of the targeted neural tissue. In this illustrative embodimentsthat follow, the electrode body 902 is adapted to fit within a DRG 40(FIG. 20D) or a ganglion of the sympathetic chain (FIG. 20C). Theelectrode 912 may be placed in any location on the electrode body 902 toobtain the desired stimulation or modulation level. Additionally, theelectrode 912 may be placed so that modulation or stimulation energypatterns generated by the electrode 912 will remain within or dissipateonly within the targeted neural tissue.

A securing ring 920 is used to hold the electrode body 902 in positionwithin and relative to the targeted neural tissue. The securing ring 920is ring shaped having an annulus 922. In some embodiments, the innersurface 942 is used as a friction locking surface to engage and hold theelectrode body 902. In other embodiments, the inner surface 942 containsa surface treatment to secure the electrode body. In still otherembodiments, the inner surface 942 is adapted to mechanically engagewith and secure the electrode body 902. The securing ring 920 may beformed from a suitable elastic or inelastic material that may be securedto the electrode body 902 and the outer layer of the targeted neuraltissue to help prevent electrode pull out or dislodgement. The securingring 920 may be formed from a biocompatible material suited to gluing ormechanically affixing the ring 920 to the electrode body 902 and thetissue outer layer. The securing ring 920 may be present during orpositioned after the electrode 900 is implanted into the targeted neuraltissue. In one alternative embodiment, the securing ring 920 is securedto the DRG outer layer and has a complementary engaging featurepositioned to engage with an engaging feature on the electrode 900. Theelectrode body 902 advances through the securing ring annulus 922 andinto the DRG 40 until the complementary engaging features engage andstop further distal motion of the electrode body 902 into the DRG. Thecomplementary engaging features may be used alone or in combination withanchors 910 to assist in electrode 900 placement within neural tissuesuch as a DRG or other ganglion.

FIGS. 20C and 20D illustrate electrode embodiments adapted forimplantation through targeted neural tissue illustrated in a sectionview of the spinal cord 13. Additional details of the various portionsof the spinal cord section 14 are described below with regard to FIG.38. Also illustrated in these views are exemplary sensory pathways 52/54and motor pathways 41P within peripheral nerve 44 and roots 41/42 andentering the spinal cord. Alternative implantation sites and stimulationalternatives are described in U.S. Pat. No. 6,871,099, incorporatedherein by reference in its entirety.

In the illustrative embodiment of FIG. 20C, the electrode 900 ispositioned to remain in a non-central location within the targetedneural tissue. In this embodiment, the targeted neural tissue is aganglion 992 within the sympathetic chain 990. Additional details andspecific targeted neural tissue within the sympathetic chain aredescribed below with regard to FIGS. 32 and 33. The electrode 912 isplaced on or in the electrode body 902 so that when the electrode body902 passes through the ganglion 992 and is seated within the securingring 920 the electrode 912 is in the desired position within theinterior of the ganglion 992. Other electrode 912 placement within thetargeted neural tissue is possible, for example, by varying the lengthof the electrode body 902, the angle of penetration into the targetedneural tissue or the position of initial penetration into the targetedneural tissue.

In the illustrative embodiment of FIG. 20D, the electrode 900 ispositioned to remain in a generally central location within the targetedneural tissue. In this embodiment, the targeted neural tissue is a DRG40. The electrode 912 is placed on or in the electrode body 902 suchthat when the electrode body 902 is seated within the securing ring 920,then the electrode 912 is in the middle of about the middle or centerthe DRG 40. As before the securing ring 920 and flat anchor 911 securethe electrode 900 in the desired position within the DRG 40. The flat orflap anchor 911 provides similar functionality as the anchor 910. Theanchor 911 has flat anchors rather than the curved anchors 910.

In some embodiments, the stimulation electrode tip may be coated with apharmacological agent. In the embodiment illustrated in FIG. 21, acoating 130 covers that portion of the electrode within the DRG 40. Inother embodiments, less or more of the electrode or other implantedcomponents may be suitably coated to achieve a desired clinical outcome.FIG. 21 also illustrates a coating 130 on the electrode shaft or portionof the electrode exterior to the DRG. The coating 132 may be the same ordifferent than the coating 130. For example, the tip coating 130 mayinclude a distal coating containing an agent to aid in the effectivestimulation of the DRG. The tip coating 130 may also include a moreproximal coating portion (i.e., near where the electrode pierces thedura) that contains an agent to prevent fibrous growth about theelectrode. In a further embodiment, the shaft coating 132 would alsocontain an agent to prevent fibrous growth about the electrode.Additionally, the shaft coating 132 may be selected based on providing apharmacological agent to interact with the tissue in the ventral root(i.e., the implantation technique in FIG. 11) or within the peripheralnerve sheath.

Examples of desired clinical outcomes provided by pharmacological agentsused as coatings include but are not limited to reduction of scar tissuedevelopment, prevention of tissue growth or formation on the electrode,anti-inflammation, channel blocking agents and combinations thereof orother known pharmacological agents useful in treatment of pain, orneurological pathologies. In other alternative embodiments, thepharmacological agent may include other compounds that, when placedwithin the body, allow the pharmacological agent to be released at acertain level over time (i.e., a time released pharmacological agent).In some embodiments, the pharmacological agent is an anti-inflammatoryagent, an opiate, a COX inhibitor, a PGE2 inhibitor, combinationsthereof and/or another suitable agent to prevent pathological painchanges after surgery. Other suitable pharmacological agents that may beused include those used to coat cardiac leads, including steroid eludingcardiac leads or other agents used to coat other implantable devices.

Embodiments of the present invention include direct stimulation of anerve root ganglion or other neurological structure while releasing apharmacological agent from an electrode used to provide stimulation. Inone embodiment, the pharmacological agent is released before theelectrode is activated. In other embodiments, the pharmacological agentis released after or during the electrode is activated. In still otherembodiments, the pharmacological agent is pharmacologically active inthe nerve root ganglion during stimulation of the nerve root ganglion.It is to be appreciated that embodiments of the present invention may bealtered and modified to accommodate the specific requirements of theneural component being stimulated. For example, embodiments of thepresent invention may be used to directly stimulate a dorsal rootganglion or a nerve root ganglion of the sympathetic system using theappropriate pharmacological agents, agent release patterns and amountsas well as stimulation patterns and levels.

Turning now to FIG. 22, various stimulation mechanisms are shown. Whilethese various mechanisms potentate pain, each of them acts on theprimary sensory neuron. The primary modulator of this cell is its cellbody, the DRG 40. One aspect of the present invention is toadvantageously utilize the anatomical placement of the DRG 40 within thenervous system to complement other treatment modalities. In anotherembodiment, stimulation of the DRG 40 as described herein is used inconjunction with a substance acting on a primary sensory neuron. Asshown, the other mechanisms are nearer to the illustrated tissue injurythan the DRG cell body 40. Put a different way, the DRG 40 is upstream(i.e., closer to the brain/spinal cord 13) of the other pain mechanisms.Thus, this is another illustration of how upstream DRG stimulation maybe used to block and/or augment another pain signals.

Electrophysiological studies suggest that Prostaglandin E2 (PGE2),produced by COX enzymes, increases the excitability of DRG neurons inpart by reducing the extent of membrane depolarization needed toactivate TTX-R Na⁺ channels. This causes neurons to have morespontaneous firing and predisposed them to favor repetitive spiking(translates to more intense pain sensation). Also illustrated here ishow other pro-inflammatory agents (Bradykinin, Capsaicin on theVanilloid Receptor [VR1]) converge to effect the TTX-R NA⁺ channel.Opiate action is also upstream from the TTX-R Na⁺ channel modulation.Embodiments of the present invention advantageously utilize aspects ofthe pain pathway and neurochemistry to modify electrophysiologicalexcitability of the DRG neurons where electrical stimulation is coupledwith pharmacological agents (electrical stimulation alone or incombination with a pharmacological agent) to optimize the efficacy ofthe stimulation system.

Synergy of electrical and pharmacological modulation may also beobtained using a number of other available pharmacological blockers orother therapeutic agents using a variety of administration routes incombination with specific, directed stimulation of a nerve rootganglion, a dorsal root ganglia, the spinal cord or the peripheralnervous system. Pharmacological blockers include, for example, Na⁺channel blockers, Ca²⁺ channel blockers, NMDA receptor blockers andopioid analgesics. As illustrated in FIGS. 23A and 23B, there is anembodiment of a combined stimulation and agent delivery electrode. Notethe bipolar electrodes 115B on the tip, the coating 130 and the beveledtip shape for piercing the dura during implantation. The electrode tipis within the DRG epineurium 72 and well positioned to modify and/orinfluence c-fiber 55 responsiveness. In the illustration, circlesrepresent Na⁺ ions, triangles represent Na⁺ channel blockers (such as,for example, dilantin—[phenytoin], tegretol—[carbamazapine] or otherknown Na⁺ channel blockers). As the agent is released from coating 130,receptors on c-fiber 55 are blocked thereby decreasing the response ofthe c-fiber below the response threshold (FIG. 23B). Because theactivation potential of the c-fiber has been lowered, the largerdiameter A-fiber is preferentially stimulated or the response of theA-fiber remains above the threshold in FIG. 23B.

Embodiments of the present invention also provide numerous advantageouscombinational therapies. For example, a pharmacological agent may beprovided that acts within or influences reactions within the dorsal rootganglia in such a way that the amount of stimulation provided byelectrode 115B may be reduced and yet still achieve a clinicallysignificant effect. Alternatively, a pharmacological agent may beprovided that acts within or influences reactions within the dorsal rootganglia in such a way that the efficacy of a stimulation provided isincreased as compared to the same stimulation provided in the absence ofthe pharmacological agent. In one specific embodiment, thepharmacological agent is a channel blocker that, after introduction, thec-fiber receptors are effectively blocked such that a higher level ofstimulation may be used that may be used in the presence of the channelblocking agent. In some embodiments, the agent may be released prior tostimulation. In other embodiments, the agent may be released during orafter stimulation, or in combinations thereof. For example, there may beprovided a treatment therapy where the agent is introduced alone,stimulation is provided alone, stimulation is provided in the presenceof the agent, or provided at a time interval after the introduction ofthe agent in such a way that the agent has been given sufficient time tointroduce a desired pharmacological effect in advance of the appliedstimulation pattern. Embodiments of the stimulation systems and methodsof the present invention enable fine tuning of C-fiber and Aβ-fiberthresholds using microelectrodes of the present invention havingpharmacological agent coatings coupled with electrical stimulation.Representative pharmacological agents include, but are not limited to:Na⁺ channel inhibitors, Phenytoin, Carbamazapine, Lidocaine GDNF,Opiates, Vicodin, Ultram, and Morphine.

FIGS. 23C and 23D illustrate alternative embodiments for combinationneurostimulation and pharmacological agent delivery systems. Additionaldetails of the controller and pulse generated systems suitable for theseoperations are described below with reference to FIGS. 26-29. Whiledescribed using combined pump and reservoir delivery systems, it is tobe appreciated that the pump for moving the pharmacological agent fromthe reservoir to and out of the electrode and the reservoir for storingthe pharmacological agent before delivery may be two separate componentsthat operate in a coordinated fashion. Pumps and reservoirs may be anyof those suited for controlled delivery of the particularpharmacological agent being delivered. Suitable pumps include any deviceadapted for whole implantation in a subject, and suitable for deliveringthe formulations for pain management or other pharmacological agentsdescribed herein. In general, the pump and reservoir is a drug deliverydevice that refers to an implantable device that provides for movementof drug from a reservoir (defined by a housing of the pump or a separatevessel in communication with the pump) by action of an operativelyconnected pump, e.g., osmotic pumps, vapor pressure pumps, electrolyticpumps, electrochemical pumps, effervescent pumps, piezoelectric pumps,or electromechanical pump systems. Additional details of suitable pumpsare available in U.S. Pat. Nos. 3,845,770; 3,916,899; 4,298,003 and6,835,194, each of which is incorporated herein by reference in theirentirety.

FIG. 23C illustrates a combined system controller and pulse generator105B adapted to control the delivery of pharmacological agents from theagent reservoir and pump 195. The pharmacological agent pumped from theagent reservoir and pump 195 travels via a dedicated conduit into acommon supply 110F, through a strain relief 122F and into the agent andstimulation electrode 2310. The common supply 110F may be a single linecontaining both electrode control and power signals from the controller105B as well as agent delivered from the pump 195 or there could be twoseparate lines joined together. Regardless of configuration, commonsupply 110F simplifies implantation procedures because a single line isused to connect the electrode 2310 to the controller 105B and the pump195.

The combination neurostimulation and pharmacological agent deliveryelectrode 2310 includes a body 2312 adapted to fit within targetedneural tissue. In this illustrative embodiment, the electrode body 2310is adapted to fit within a DRG 40. An electrode 2318 is positioned on orin the electrode body 2312 or may be the electrode body 2312. Theelectrode 2318 is adapted to receive signals and power from the pulsegenerator 105B via the common supply 110F. The electrode 2318 may beplaced in any location on the electrode body 2312 to obtain the desiredstimulation or modulation level. Additionally, the electrode 2318 may beplaced so that modulation or stimulation energy patterns generated bythe electrode will remain within or dissipate only within the targetedneural tissue. In this illustrative embodiment, the electrode 2318 ispositioned to remain in a generally central location within the targetedneural tissue. In this embodiment, the targeted neural tissue is a DRG40. The electrode 2318 is placed on or in the electrode body 2312 suchthat when the electrode 2310 is seated within the securing ring(described below), then the electrode 2318 is in the middle of about themiddle or center the DRG.

A securing ring 2315 is used to hold the electrode body 2312 in positionwithin and relative to the DRG 40. The securing ring 2315 may be formedfrom a suitable elastic or inelastic material that may be secured to theelectrode body 2312 and the outer DRG layer to help prevent electrodepull out or dislodgement. The securing ring 2315 may be formed from abiocompatible material suited to gluing or mechanically affixing thering 2315 to the electrode body 2312 and the DRG outer layer. Thesecuring ring 2315 may be present during or positioned after theelectrode 2310 is implanted into the DRG. In one alternative embodiment,the securing ring is secured to the DRG out layer and has acomplementary engaging feature positioned to engage with an engagingfeature on the electrode 2310. The electrode body 2312 advances throughthe securing ring 2315 and into the DRG 40 until the complementaryengaging features engage and stop further distal motion of the electrodebody 2312 into the DRG. The complementary engaging features may be usedto prevent an electrode 2310 intended to be positioned within a DRG frompiercing through a DRG.

There is at least one conduit or lumen (not shown) within the electrodebody 2312 that provides communication from the portion of the commonsupply 110F containing the pharmacological agent to the distal opening2316. In operation, pharmacological agent(s) within the pump/reservoir195 are delivered, under the control of controller 105B, to the commonsupply 110F, through the electrode body 2312 and out the distal opening2316 into the DRG interior. Note that this embodiment of the distalopening 2316 contains a beveled edge that may be used to pierce the DRGduring the implantation procedure.

FIG. 23D describes several alternative embodiments suited to combinedneurostimulation and pharmacological agent delivery systems andelectrodes.

In contrast to FIG. 23C that uses a combined controller, pulse generatorand battery 105B, the configuration in FIG. 23D provides a distributedsystem similar to those described with regard to FIGS. 28 and 29. Apulse generator and controller 105C and a pharmacological agentreservoir and pump 2395 receive power from battery 2830 using suitableconnections 2307 and 2305, respectively. The pharmacological agentreservoir and pump 2395 may have its own controller operatedindependently of the controller/generator 105C, have its own controlleroperated under the control of the controller/generator 105C (i.e., in amaster/slave relationship) or be operated under the control of thecontroller/generator 105C. Electrode 912 receives stimulation power fromgenerator 105 c via leads 110. Perfusion ports 928 are connected via oneor more conduits (not shown) within the electrode body 902 and theconduit 2396 to the pharmacological agent reservoir and pump 2395.

The embodiment of electrode 900A is similar to the electrode 900 of FIG.20A. Electrode 900A also includes perfusion ports 928 within theelectrode body 902 that are in communication with the contents of thepump and reservoir 2395 via the conduit 2396. The electrode body 902 islong enough for implantation through targeted neural tissue. Whileillustrated implanted generally central to a DRG 40, it is to beappreciated that the electrode body 902 may be longer or shorter toaccommodate different sizes of targeted neural tissue or differentplacement within neural tissue. For example, FIG. 20C illustrates anembodiment of electrode 900 implanted in a non-central position within aganglion of the sympathetic chain. The electrode 900A includes aproximal end 904 with tip 908 and anchors 910. A securing ring 920(described above) is provided to secure the electrode body 902 to orrelative to the DRG 40. The anchors 910 may be in a first or stowedposition against the electrode body 902 during insertion through the DRGand then be moveable into a second or deployed position away from theelectrode body 902. In the deployed position (FIG. 23D) the anchors 910resist the movement of the electrode 900A out of the DRG 40. Numerousalternative anchor configurations are possible. Anchor 910 could be aseries of individual struts arrayed in a circular pattern or struts withmaterial between them similar to the construction of an umbrella. Anchor910 could also be a single anchor.

The electrode 912 and perfusion ports 928 may be positioned along theelectrode body 902 in any position suited for the delivery ofneurostimulation and pharmacological agents. In the illustratedembodiment, the electrode 912 is positioned generally central within theDRG and the perfusion ports 928 are near the distal end of the electrodebody 902. Other configurations are possible and more or fewer electrodesand perfusion ports may be used in other embodiments. For example, aperfusion port 928 could be located near the center of the DRG while anelectrode 912 could be located elsewhere on the electrode body 902 so asto minimize the stimulation energy transmitted beyond the DRG and intosurrounding tissue. One or more electrodes 912 could be positioned alongthe electrode body 902 so that the stimulation energy remained within(i.e., nearly completely attenuated within) the DRG 40 or other targetedneural tissue.

In one specific embodiment, the distal tip 908 has a point suited forpiercing the dura layers to provide access for the electrode body 902through the DRG. The tip 908 is advanced through the DRG until theanchors 910 pass through the opening formed by the tip 908 and extend asshown in FIG. 23D. Once the anchors 910 are through the DRG andextended, the electrode body 902 may be withdrawn slightly to engage theanchors 910 against the DRG dura. Thereafter, the securing ring 920 isadvanced into position around the electrode body 902 and against theouter layer of DRG 40. When implanted into the DRG 40, electrode 900A isheld in place using the anchors 910 and the securing ring 920. In otherembodiments, the securing ring 920 may be used without the anchors 910.In another embodiment, the anchors 910 are used without the securingring 920 or the securing ring 920 is replaced by another set of anchorsthat are adapted to secure the proximal end of the electrode body 902 toor in proximity to the DRG.

FIG. 24 is a table that includes several exemplary infusionpharmacological agents. The pharmacological agents are listed along theleft side. Moving to the right, closed circles and open circles are usedto indicate the level of support for using a particular pharmacologicalagent with a particular type of pain or other condition. Closed circlesindicate evidence from controlled trials or several open-label trialsand general acceptance or utility. Open circles indicate a lessextensive base of evidence. For example in the treatment of restless legsyndrome (RLS), benzodiazepines have evidence of general acceptance orutility while gabapentin has a less extensive base of evidence. Theseand other pharmacological agents may be provided into the body to have acooperative pharmacological result on the neural tissue(s) either aloneor in combination with stimulation provided by embodiments of thepresent invention. In some embodiments, the pharmacological agent isprovided at the stimulation site and in other embodiments thepharmacological agent is provided using a stimulation electrodeembodiment adapted to deliver one or more pharmacological agents.

Consider the following specific example. Nociceptors express a specificsubclass of voltage-gated sodium channel. These TTX-R Na⁺ channels arebelieved to contribute significantly to action potential firing rate andduration in small-diameter sensory neurons (i.e., c-fibers). Embodimentsof the present invention may provide the appropriate channel blocker tosynergistically improve neurostimulation capabilities. For example, acombination stimulation and release of a pharmacological agent may beused to provide Na channel blockers directly within the dorsal rootganglia interfascicular space, adjacent to c-fiber or within apharmacologically active position such that the agent interacts with thechannel.

Embodiments of the present invention also enable the advantageous use ofion channels in the nervous system as targets for pharmacological agentscombined with selective direct stimulation. Na⁺ channels and gabapentinsensitive Ca²⁺ channels are upregulated after nerve-injury. Channelblockers can suppress abnormal C-fiber neural excitability. Na⁺ and Ca⁺channel targets distributed along the pain pathway are illustrated inFIG. 25. Embodiments of the present invention advantageously utilize thespecific anatomy and features of the dorsal root ganglia (DRG) toimprove the efficacy of pharmacological agents. In one specific example,note that the DRG contains both TTX-sensitive NA⁺ channels (Nav1.3),TTX-resistant Na⁺ channels (1.8, 1.9), and gabapentin sensitive Ca²⁺channels. FIG. 25 shows a number of dorsal root ganglia, peripheralnervous system and spinal cord afferent pain pathways. Note thealterations in voltage-dependent Na⁺ and Ca²⁺ channel subunits afterchronic nerve injury associated with neuropathic pain. In addition,there is an increase in the expression of Nav1.3 channels and Na⁺channel 3 (Nav 3) and Ca²⁺ channel 2-1 (Cav 2-1) subunits in dorsal rootganglion neuron cell bodies, and in the expression of Nav1.3 insecond-order nociceptive neurons in the spinal cord dorsal horn 37. Thetetrodotoxin-resistant Na⁺ channel subunits Nav1.8 and Nav1.9 are alsoredistributed from dorsal root ganglion neuron cell bodies to peripheralaxons and pain receptors at the site of injury. These changes arethought to result in spontaneous ectopic discharges and lower thethreshold for mechanical activation that leads to paraesthesias,hyperalgesia and allodynia.

In one aspect of the present invention, these channels are the target ofa stimulation provided by embodiments of the systems and stimulationmethods of the present invention. The stimulation may include electricalstimulation alone, a pharmacological agent delivered directly or via theDRG, a pharmacological agent delivered directly or via the DRG incombination with electrical stimulation, or electrical stimulation ofthe DRG in combination with the delivery of a pharmacological agentelsewhere in the pain pathway. In one particular embodiment, delivery ofa pharmacological agent elsewhere in the pain pathway is upstream of thedorsal root ganglion or the nerve root ganglion being stimulated. Inanother embodiment, delivery of a pharmacological agent elsewhere in thepain pathway is downstream of the dorsal root ganglion. In anotherspecific embodiment, stimulation is provided to a nerve ganglion in thesympathetic nervous system and a dorsal root ganglion up stream of orotherwise positioned to influence or block signals originating from thenerve ganglion.

Alternative embodiments of the methods and systems of the presentinvention may be used to repair or assist in the repair of neurologicaltissue in the spinal cord.

In another aspect of the present invention, there is provided methodsand systems for the selective neurostimulation of the dorsal rootganglia for the regeneration of neurological tissue. For example,electrical stimulation may be provided selectively to the DRG, a portionof the DRG or in proximity to the DRG with or without a pharmacologicalagent to produce conditions within the DRG to assist in, encourage orotherwise promote the regeneration of neurological tissue.

In a specific embodiment where pharmacological agents may be provided byembodiments of the present invention, there is provided a method and/orsystem to induce intraganglionic cAMP elevation for the regeneration ofsensory axons utilizing the mechanisms suggested by Neumann S, Bradke F,Tessier-Lavigne M, Basbaum A I. In the article entitled, “Regenerationof Sensory Axons Within the Injured Spinal Cord Induced byIntraganglionic cAMP Elevation. (see Neuron. 2002 Jun. 13; 34(6):885-93,incorporated herein by reference in its entirety.) The work of Neuman etal. demonstrated the regeneration of the central branches of sensoryneurons in vivo after intraganglionic injection of db-cAMP. Horizontalsections through a lesion site taken from db-cAMP-injected animals showsregenerating fibers. A neurostimulation electrode adapted for deliveryof a pharmacological agent may be used for intraganglionic delivery ofdb-cAMP. Intraganglionic delivery of db-cAMP may be accomplished usingany of the techniques described herein for the delivery of apharmacological agent including, for example, a coating on all or partof an electrode body or the use of suitably positioned perfusion ports.

FIG. 26 illustrates an embodiment of a pulse generator 105 according toone aspect of the present invention. Similar to conventional stimulationpulse generators, communication electronics 102 have a receiver forreceiving instructions and a transmitter for transmitting information.In one embodiment, the receiver and the transmitter are implantable inthe body and adapted receive and transmit information percutaneously.The control electronics 106 includes a microcontroller 103 havingconventional features such as program memory 103.1, parameter andalgorithm memory 103.2 and data memory 103.3. A battery 130 is alsoprovided and may be located with and part of the pulse generator (i.e.,FIG. 27) or implanted at a location separate from the pulse generator(i.e., FIG. 28). Switches 109 are provided to couple stimulation energyfrom the DC-DC converter 113 to the stimulation sites (i.e., electrodeslocated at STIM1-STIM4) under the control of the microcontroller 103.

Programmable parameters are modified in accordance with transcutaneousRF telemetry information received by communication electronics 102. Thetelemetry information is decoded and used by the control electronics tomodify the pulse generator 105 output as needed. The output of the pulsegenerator or a stimulation program may be modified dynamically. Painoften correlates to certain activities such as walking, bending orsitting. An activity level sensor may be used to detect the amount ordegree of activity. The level of activity could be an input todynamically modify the stimulation program to determine the appropriatelevel of stimulation. Alternatively or additionally, differentpre-programmed stimulation algorithms may be designed for an individualpatient based on that specific patient's pattern of activity.Pre-programmed stimulation algorithms may be stored in an appropriatemedium for use by a stimulation system described herein. Conventionaltranscutaneous programming techniques may also be used to update, modifyor remove stimulation algorithms.

Pain often correlates to certain positions such as standing or layingdown. A position sensor may be used to detect position of the patient.The position of the patient could be an input to the stimulation controlsystem to dynamically modify the stimulation program to determine theappropriate level of stimulation. One example of such a sensor is amulti-axis accelerometer. A conventional 3 or 4 axis accelerometer couldbe implanted into a patient or maintained on the patient to provideposition, activity level, activity duration or other indications ofpatient status. The detected indications of patient status could in turnbe used in determining stimulation level and pattern. The positionsensor can be set up or calibrated once positioned or implanted on or ina person. The calibration aids the sensor in correctly recognizing theperson's orientation and activity levels.

Optionally, a position sensor 108 is located within the same physicalhousing as implantable generator. If desired, the position sensor may belocated elsewhere on the body in an implanted location or may be wornexternally by the person. Position information from the position and/oractivity sensor 108 is provided to the pulse generator 105 usingsuitable means including direct connections or percutaneoustransmission. Although a number of embodiments are suitable, thepreferred mode employs, by way of example and not to be construed aslimiting of the present invention, one or more accelerometers todetermine patient state including, at least, the ability to sensewhether the person is erect or recumbent. Additionally, the positionsensor could be adapted to provide an indication of activity or level ofactivity such as the difference between walking and running. In anotherembodiment, a position sensor 108 may be positioned to sense specificmotion such as activity of a particular part of the body to detectspecific movement of a body part or limb that, for example, isundergoing post-surgical physical therapy. Using this position sensorembodiment, when the person started activity related to physicaltherapy, the sensor would detect such activity and provide theappropriate stimulation. In additional alternatives, the position and/oractivity sensor includes one or more multi-axis accelerometers.

As discussed above, microelectrode embodiments of the present inventionhave electrode sizes and surface areas that are considerably smallerthat conventional stimulation electrodes so that they may be implantedaccording to the methods described herein. As discussed above, thesmaller electrode size leads to increased electrical impedance and aneed for voltages above 15 volts, above 20 volts or even up to as muchas 40 volts in order to provide sufficient stimulation current to themicroelectrode. Conventional pulse generators employ capacitiveswitching arrays to provide voltages up to 12 v from a 3 v battery forconventional neurostimulation systems. It is believed that the largeelectrical losses introduced by the switches used in conventionalcapacitive systems would render them incapable of providing sufficientcurrent to drive the microelectrodes of the present invention. As such,the pulse generator 105 departs from conventional pulse generators byusing a DC-DC converter to multiply the battery voltage up to the rangesneeded to operate the stimulation systems described herein.

In one embodiment of the pulse generator of the present invention, thereis at least one switch 109 connected to at least one implantableelectrode having an impedance greater than 2,500 ohms. There is alsoprovided a DC-DC converter adapted to provide a stimulation signal tothe at least one implantable electrode under the control of thecontroller 103 that is configured to control the output of the DC-DCconverter 113. Additionally, the pulse generator, the at least oneswitch, the DC-DC converter and the controller are implantable in thebody. In another aspect, the controller 103 controls the output of theDC-DC converter 113 to deliver a stimulation signal according to analgorithm for blocking pain signals. In one aspect, the DC-DC converteris configured to provide a voltage from 0 volts to 30 volts. In anotheraspect, the DC-DC converter is configured to provide a voltage from 0volts to 40 volts.

FIG. 27 illustrates one embodiment of an electrode connector accordingto the present invention. The electrode connector 120 has a proximateend 123 adapted to connect with a pulse generator 105A and distal end121 adapted to connect with the electrode connector 126. The electrodeconnector distal 121 end is adapted to connect to a plurality ofmicroelectrode leads 110/connectors 126 depending upon how manymicroelectrodes 115 are used. Optionally, a portion of the electrodeconnector 120 may be configured as a return electrode in someembodiments.

In conventional stimulation systems, the stimulation electrode leads areconnected directly to the pulse generator resulting in an implantationprocedure that includes tunneling multiple leads from the pulsegenerator to each electrode. This technique has the added shortcoming ofmultiple connection points into the pulse generator each one required tobe sealed and a source of potential wear. In contrast, embodiments ofthe present invention utilize fine micro leads 110 and microelectrodes115 that would likely hinder the success of conventional tunnelingprocedures. Rather than the conventional tunneling of multipleelectrodes and their leads, the electrode connector 120 is a flexibleelectrical connector used to bridge the distance between the site wherethe pulse generator is implanted and the one or more stimulation siteswhere the microelectrodes will be implanted. It is to be appreciatedthat the electrode connector is sufficiently long to extend from thepulse generator implanted at a first anatomical site to themicroelectrode implanted at a second anatomical site.

The pulse generator 105A differs from conventional pulse generators inthat is has a single connection point to the electrode connector rathermultiple connection points to each stimulation electrode.Advantageously, the fine micro leads and microelectrodes are thusimplanted and span a distance now made much shorter by the electrodeconnector 120. The microelectrode leads 110 now only span a distancebetween the electrode connector distal end 121 and the microelectrode115 at the nerve root ganglion implantation site.

FIG. 27 also illustrates an embodiment of a stimulation component. Thestimulation component includes a proximal connector 126, a distalelectrode 115 configured to be implanted within the body at astimulation site and an electrical lead 110 connected to the proximalconnector and the distal electrode. The distal electrode may be, forexample, a mono-polar electrode or a bi-polar electrode. In someembodiments, there is also provided a strain relief mechanism inproximity to the stimulation site and/or a fixation element adapted toreduce the amount of movement of the electrical lead proximal to afixation point in an anatomical structure proximal to the stimulationsite (See e.g., 12A/B, 13A, 14A). The proximate connector 126 is adaptedto connect with the electrode connector distal end 121.

In still further embodiments, the stimulation component may also includean anchoring mechanism proximal to the distal electrode (e.g.,deformable anchor 117 in FIG. 13B, 14B). In some embodiments, theanchoring mechanism is adapted to anchor the distal electrode within thestimulation site and may optionally be integrally formed with the distalelectrode. The anchoring mechanism is formed from a polymer, a siliconeor other flexible, biocompatible material. In some embodiments, theanchoring mechanism and/or the electrode body is formed from a flexible,biocompatible material that has been adapted to include a radio opaquematerial. Suitable biocompatible materials may biocompatible polymericbiomaterials featuring radio-opacity or other polymeric biomaterialsmade radio-opaque through addition of a ‘contrast agent’, usually anon-toxic salt or oxide of a heavy atom.

FIG. 28 illustrates another stimulation system embodiment of the presentinvention. In the illustrative embodiment, a pulse generator 2806 isconnected to four individually controlled microelectrodes 115 implantedin four separate nerve root ganglion, here dorsal root ganglions DRG1through DRG4. The innovative stimulation system of FIG. 28 differs fromconventional stimulation systems in that the battery 2830 is separatefrom the pulse generator 2806. An electrical connection (e.g., wires2804) suited to carry the battery power extends from the battery 2830 tothe pulse generator 2806. A microelectrode lead 110 is connectedproximally to the pulse generator 2806 using connectors 2812 anddistally to a microelectrode 115. The pulse generator 2806 includessimilar functionality of earlier described pulse generator embodimentssuch as a DC-DC converter configured to provide a voltage from 0 voltsto 30 volts, a voltage from 0 volts to 40 volts or other suitablevoltage ranges to drive microelectrodes described herein. The battery2830, the pulse generator 2806 separate from the battery, the electricalconnections 2804, the microelectrode lead 110 and the microelectrode 115are adapted to be implanted in the body.

Additional embodiments of the local pulse generator 2806 have a compactsize that enables implantation of the pulse generator 2806 in proximityto the stimulation site. Implanting the local pulse generator 2806closer to the implantation site of the microelectrodes 115 desirablyallows the use of shorter microelectrode leads 110. Embodiments of thepulse generator 2806 are sufficiently small to allow implantation in theback near the spinal levels to be stimulated, the upper back near theC1-C3 levels for migraine relief (FIG. 30). In one specific embodiment,the pulse generator 2806 has an overall volume of less than 200 mm³. Inanother specific embodiment, at least one dimension of the pulsegenerator 2806 is 2 mm or less or at least one dimension of the pulsegenerator 2806 is 10 mm or less.

One embodiment of a multiple pulse generator system is illustrated inFIG. 29. The multiple pulse generator embodiment is similar to thesystem of FIG. 28 with the addition of a second pulse generator 2806Bconnected to the first pulse generator 2806A at connection points 2810using connectors 2814. As with the earlier system, the second pulsegenerator 2806B is separate from the battery 2830. Additionally, thereare provided microelectrode leads 110 connected proximally usingconnectors 2812 to the second pulse generator 2806B and distally tomicroelectrodes 115. The microelectrodes 115 are implanted within nerveroot ganglia, here, dorsal root ganglia at implantation sites DRG5-DRG8.FIG. 29 illustrates eight implanted electrodes in separate implantationsites that could include dorsal root ganglion, nerve root ganglion ofthe sympathetic nervous system or other stimulation sites within thebody.

It is to be appreciated that in one aspect the pulse generator 2806 andthe second pulse generator 2806B are independently programmable. Inanother aspect, the pulse generator 2806A and the second pulse generator2806B are adapted to operate in a master-slave configuration. Numerouscoordinated stimulation patterns are possible for each electrode of apulse generator or of all the electrodes in the system. In still furtheraspects, the activation of one microelectrode is coordinated with theactivation of a second microelectrode. In one specific aspect, themicroelectrode and the second microelectrode are activated by the samepulse generator. In another specific aspect, the microelectrode isactivated by the pulse generator 2806A and the second microelectrode bythe second pulse generator 2806B in a coordinated manner to achieve atherapeutic outcome. For example, the microelectrode is active when thesecond microelectrode is active or the microelectrode is inactive whenthe second microelectrode is active. In still further embodiments, themicroelectrode is implanted in a dorsal root ganglion and the secondmicroelectrode is implanted in a nerve root ganglion of the sympatheticnervous system. It is to be appreciated that the systems of FIGS. 27 and28 may be configured as discussed above with regard to FIGS. 3-7.

In additional alternative aspects, specific embodiments of the presentinvention may be used to provide direct stimulation alone or incombination with released therapeutic agents as described herein for thetreatment of headaches, migraine etc. As such, embodiments of thepresent invention may be used to provide direct, selective DRG, spinalcord and/or peripheral nervous system stimulation (using stimulationalone or in combination with the delivery of a therapeutic agent asdescribed herein) to all, part or a combination of the C1-C3 levels toprovide relief, reduction or mitigation of pain resulting from headache,migraine or other such related conditions. There is provided a method ofstimulating neural tissue to treat a condition by stimulating anelectrode implanted to stimulate only a dorsal root ganglion on a spinallevel wherein the stimulation treats the condition. As illustrated inFIG. 30, the spinal level comprises C1, C2 or C3 and the condition is aheadache, or more specifically, a migraine headache.

In another alternative aspect, embodiments of the present inventionprovide sensory augmentation as a treatment for diabetic neuropathy. Inone embodiment, direct stimulation of the DRG, spinal cord and/orperipheral nervous system using the techniques described herein areprovided to stimulate or otherwise generate a type of stochasticresonance that will improve, enhance or provide added neurologicalstimulation. Stochastic resonance is the addition of noise to a systemto improve signal clarity. For example, the introduction of directneurological stimulation to the appropriate DRG, group of DRG, thespinal cord and/or peripheral nervous system may provide, for example,improved vestibular balance or other improvement or mitigation of acondition induced by diabetic neuropathy. The added neurologicalstimulation (either stimulation alone or in combination with therapeuticagent(s)) may be used, for example, to improve the nerve fiber functionof nerve fibers damaged, improperly functioning or otherwise impaired asa result of diabetic neuropathy. Exemplary stimulation patterns inducedutilizing direct stimulation techniques described herein to help raisethe sub-threshold signal (FIG. 31A) to or above the threshold level(FIG. 31B).

In other embodiments of the present invention there are provided methodsof treating physiological disorders by implanting at least onestimulation electrode at a specific location along the sympathetic nervechain. Preferably, the present invention provides a method oftherapeutically treating a variety of physiological disorders orpathological conditions by surgically implanting an electrode adjacentor in communication to a predetermined site along the sympathetic nervechain on the affected side of the body or, if clinically indicated,bilaterally. FIG. 32 illustrates a schematic of the autonomic nervoussystem illustrating sympathetic fibers and parasympathetic fibers,including several nerve root ganglion.

Accordingly, embodiments of the present invention may be used inconjunction with other neurostimulation techniques by combining anupstream stimulation using specific DRG stimulation of the presentinvention with another stimulation acting downstream of the DRGstimulation. As used herein, downstream and upstream refer to pathwayscloser to the brain (i.e., upstream) or further from the brain (i.e.,downstream). For example, several stimulation techniques are describedby Rezai in US Patent Publication No. 2002-0116030 and U.S. Pat. No.6,438,423 and by Dobak in U.S. Patent Publication NO. 2003-0181958, allof which are incorporated herein by reference. In specific aspects,embodiments of the present invention may be used to provide electricaland combinational (i.e., with a pharmacological agent) stimulation ofthe sympathetic nerve chain as described by Rezai alone (i.e., using theappropriate DRG stimulation or implanting directly into a nerve rootganglion.). Alternatively or additionally, embodiments of the presentinvention provide specific, direct stimulation of one or more DRG areused in combination with the stimulation techniques described by Rezai(i.e., conventional stimulation of the sympathetic chain using one ormore of Rezai's techniques).

FIG. 33 illustrates how embodiments of the present invention may beadvantageously utilized for neurostimulation of the sympathetic chainusing direct stimulation of the associated DRG. This aspect of thepresent invention takes advantage of the anatomical placement of the DRGrelative to the sympathetic chain in conjunction with gate controltheory described herein to direct DRG stimulation for control of thesympathetic system. Thus, selective neurostimulation techniques of thepresent invention may be advantageously employed to, for example,provide and/or augment therapeutic tools in regards to weight control,hormonal regulation, vascular perfusion, etc. Additional alternativeembodiments include the use of specific stimulation to provide organsystem autonomic modulation. Through implantation of stimulationelectrodes and systems of the present invention to stimulate theappropriate DRG upstream of the associated portion(s) of the sympatheticchain, the associated system may be controlled, modulated or influencedutilizing the electrical and/or pharmacological agent stimulationtechniques described herein.

In one specific example, by stimulating the DRG 40 associated withspinal level 13.3, the portion of the sympathetic chain associated withhormonal regulation may be altered, modified, influenced or controlled.Similarly, by stimulating the DRG 40 associated with spinal level 13.2and/or level 13.1, the portion of the sympathetic chain associated withthe gastrointestinal tract, or urinary incontinence (i.e., urinarybladder, urethra, prostate, etc.) may be altered, modified, influencedor controlled. Additionally, the direct stimulation techniques describedherein may be used to directly stimulate individual nerve ganglion ofthe sympathetic nervous system, such as, for example, the celiacganglion, superior mesenteric ganglion, inferior mesenteric ganglion andothers listed in FIGS. 32, 33 or known to those of ordinary skill. It isto be appreciated that the stimulation systems, pulse generators andmicroelectrodes and other components are modified and sized as needed toallow for direct stimulation of the ganglion including implanting intothe ganglion or within adjacent nerve sheaths leading to the ganglion.FIG. 34 illustrates the combined direct stimulation of a DRG 38 withmicroelectrode 115 as well as a suitable sized microelectrode 115implanted in a sympathetic nerve root ganglion 63. The electrodes inFIG. 34 may stimulated independently or in a coordinated fashion toachieve the desired clinical outcome or other desired result. Similar tothe discussion above for electrode placement in the DRG, electrodeplacement for the sympathetic chain may also be unilateral, bilateral,on adjacent portions of the chain or separate portions of the chain asneeded.

One aspect of the present invention is a method of modulating a neuralpathway in the sympathetic nervous system including stimulating a spinaldorsal root ganglion upstream of at least one ganglion of thesympathetic nerve chain to influence a condition associated with the atleast one ganglion of the sympathetic nerve chain. In one specificembodiment, stimulating a spinal dorsal root ganglion comprisesstimulating a spinal dorsal root ganglion upstream of at least oneganglion of the sympathetic nerve chain to influence functionalactivation of a bodily system associated with the at least one ganglionalong the sympathetic nerve chain, to influence functional activation ofan organ associated with the at least one ganglion along the sympatheticnerve chain, or to influence functional inhibition of a bodily systemassociated with the at least one ganglion along the sympathetic nervechain. In specific embodiments, the ganglion of the sympathetic nervechain is a cervical ganglion, a thoracic ganglion, or a lumbar ganglion.

In another aspect, the method of modulating a neural pathway in thesympathetic nervous system includes application of stimulation using anelectrode exposed to the spinal dorsal root ganglion epinurium. Inanother aspect, the application of stimulation is performed using anelectrode within the dorsal root ganglion. Alternatively, or inaddition, stimulation may be applied to at least one ganglion along thesympathetic nerve chain using an electrode exposed to the at least oneganglion or using an electrode implanted within the at least oneganglion or applying stimulation along the sympathetic nerve chain.

FIGS. 35, 36 and 38 illustrate how embodiments of the stimulationsystem, methods and microelectrodes described herein may beadvantageously employed for direct stimulation of the spinal cord. Thoseof ordinary skill will appreciate that a pulse generator, battery andother stimulation system components described above would be used todrive the spinal electrodes described herein. As illustrated in FIG. 35,a microelectrode 115 has been advanced through the epidural space 26through the dura matter 32 and into the spinal cord 13. In theillustrated embodiment the electrode 13 is positioned in the spinal cord13 with an anchor 124 in the vertebral body 70 along with a strainreducing element 122 (i.e., a coil of microelectrode lead 110). FIG. 36illustrates two electrodes implanted into the spinal cord 13 for directstimulation. Optionally or additionally, anchors and seals may also beprovided and are further described below with regard to FIGS. 37A, B andC. While the illustrative embodiments show an electrode implanted at adepth into the spinal cord, electrodes may be surface mounted as well.For example, electrodes may be placed in positions that just pierce theouter surface up to a depth of 1 mm or alternatively at depths from 2 mmto 12 mm or as otherwise needed to accomplish the desired stimulationtherapy or treatment.

Embodiments of the present invention provide a method of stimulating thespinal cord that includes implanting an electrode into the spinal cordand providing stimulation energy to spinal cord fibers using theelectrode. In one aspect, the stimulation energy is provided to thespinal cord using the electrodes at a level below the energy level thatwill ablate or otherwise damage spinal cord fiber. In specificembodiments, the spinal microelectrode is implanted into the cuneatefascicle, the gracile fascicle, the corticospinal tract, an ascendingneural pathway, and/or a descending neural pathway.

In another specific embodiment, a method for stimulation of the spinalcord includes piercing the spinal dura matter and placing an electrodeinto contact with a portion of the intra-madullary of the spinal cord.Additionally, the portion of the intra-madullary of the spinal cord mayinclude the cuneate fascicle, the gracile fascicle, the corticospinaltract. Additionally or optionally, the electrode may be implanted intothe portion of the intra-madullary of the spinal cord including aportion of the intra-madullary that controls pain from the upperextremities, the lower extremities, an upper spinal cord pain pathway,or a lower spinal cord pain pathway. Additionally or optionally, anelectrode may be implanted into and directly stimulate a portion of theintra-madullary of the spinal cord that influences control of an organ,such as for example, autonomic bladder stimulation, or other bodyfunction.

FIGS. 37A-37C illustrate alternatives to sealing the spinal dura 32after the dura is pierced during the electrode implantation procedure.In one aspect, the present invention provides methods of forming anopening in the spinal dura, passing the electrode through the opening inthe spinal dura and sealing the opening in the spinal dura 32.Additionally, atraumatic anchors 3717 may also be provided distal to theelectrode 3715 to assist with maintaining electrode position in thespinal cord 13 after implantation, as well as resist pull out. Theanchors 3717 may be formed from any suitable biocompatible material thatis flexible and will not contaminate the surrounding cerebral spinalfluid. In FIG. 37A, a single fibrous seal 3710 is disposed distal to theanchor 3717 against the interior wall of the dura 32. Examples ofsuitable seal materials for seals 3710, 3720 and 3725 include, forexample, tissue glue, synthetic fibers, gel foam, hydrogels, hydrophilicpolymers or other materials having fabric characteristics suited tosealing. Each of the seals described herein may be separate from orintegrally formed with an anchor 3717. FIG. 37B illustrates anembodiment where a seal 3720 is provided on the exterior wall of thedura 32. FIG. 37C illustrates the use of two seals. A seal 3725 againstthe inner dura wall and a seal 3720 against the outer dura wall.Examples of suitable seal materials for seals 3720, 3725 include:vascular suture pads, polyurethane, fluorinated polymers, biodegradablepolymers such as PLA/PGLA. Seals as described herein are adapted toprevent CSF leakage through the hole in the dura formed during electrodeimplantation. In alternative embodiments, the component passing throughthe dura after implantation (either a microelectrode shaft ormicroelectrode leads depending upon design) has a material or surfacethat engages with the seal 3717, 3720 and assists in sealing the dura.In one specific embodiment, the seal 3720 could be a fabric pad such asa vascular suture pad and the seal 3725 could be a polymer or a form oftissue glue.

FIG. 38 illustrates and summarizes numerous specific targets forstimulation and electrode placement within the nervous system. Nerves ononly one side of the spinal cord are shown. FIG. 38 illustrates severalalternative microelectrode placement locations depending upon desiredstimulation, neural response or treatment of a condition. Embodiments ofthe present invention employ appropriately small sized microelectrodesthereby enabling the selective stimulation of numerous specific portionsof the nervous system in addition to the specific embodiments describedherein. Microelectrodes are illustrated in the DRG dura (1), within theDRG through the dura (2A), within the DRG by traversing the peripheralnerve sheath (2B). The spinal cord may be stimulated by implantingelectrode(s) into ascending pathways 92, descending pathways 94 orfibers 96. Spinal cord stimulation may also be accomplished by placingmicroelectrodes into specific spinal cord regions such as the cuneatefascicle 3, gracile fascicle 4 or the corticospinal tract 5.Additionally, electrodes may be placed in the spinal cord near the rootentry into the cord, such as dorsal root 42H and ventral root 41H.Embodiments of the present invention also enable microelectrodeplacement and direct stimulation can be advantageously positioned andapplied so as to influence and/or control bodily function(s).

In some embodiments, direct stimulation refers to the application ofstimulation or modulation energy to neural tissue by placing one or moreelectrodes into contact with the targeted neural tissue. In somespecific embodiments, contact with the targeted neural tissue refers toelectrode placement on or in a nerve ganglion. In other embodiments, oneor more electrodes may be placed adjacent to one or more nerve ganglionwithout contacting the nerve ganglion. Electrode placement withoutcontacting the nerve ganglion refers to positioning an electrode tostimulate preferentially only a nerve ganglion. Stimulation ofpreferentially only a nerve ganglion refers to electrode placement orelectrode energy delivery to targeted neural tissue without passing theneurostimulation or modulation energy through an interveningphysiological structure or tissue.

Several advantages of the inventive stimulation system and methodsdescribed herein are made clear through contrast to existingconventional stimulation systems such as those described in, forexample, U.S. Pat. No. 6,259,952; U.S. Pat. No. 6,319,241 and U.S. Pat.No. 6,871,099 each of which are incorporated herein by reference.

Consider for example a conventional stimulation electrode placed withina vertebral body for stimulation of a dorsal root ganglion. A portion ofthe stimulation energy provided by an electrode so positioned will beattenuated or absorbed by the surrounding bone structure. As a result,the initial stimulation energy provided in this system must be largeenough to compensate for propagation losses through the bone while stillhaving sufficient remaining energy to accomplish the desired stimulationlevel at the dorsal root ganglion. The stimulation energy of thisconventional system will also be non-specifically applied to theintervening physiological structures such as the spinal cord, peripheralnerves, dorsal root, ventral root and surrounding tissue, cartilage andmuscle. Each of these intervening physiological structures will besubjected to the stimulation energy and may cause undesiredconsequences. In addition, each of these physiological structures willbe subjected to and may attenuate or absorb the stimulation energybefore the energy reaches the desired neural tissue.

Consider the additional examples of conventional stimulation electrodesplaced (a) within the dorsal root between the spinal dura and the spinalcord and (b) within the peripheral nerve. Neurostimulation of a dorsalroot ganglion from these positions is complicated by ways similar to theabove example. The stimulation energy provided by the electrode mustpass through or may be absorbed by numerous surrounding physiologicalstructures. A portion of the stimulation energy provided by an electrodein position (a) will be attenuated or absorbed by, for example, thesurrounding dorsal root sheath, cerebral spinal fluid and the spinalcord. The stimulation energy provided in, this system must be largeenough to compensate for propagation losses through the dorsal rootsheath, cerebral spinal fluid and protective spinal cord layers (i.e.,the spinal meninges: pia mater, arachnoid mater and dura mater) whilestill having sufficient remaining energy to accomplish the desiredstimulation level in the dorsal root ganglion. The stimulation energywill also be non-specifically applied to the spinal cord. A portion ofthe stimulation energy provided by an electrode in position (b) will beattenuated or absorbed by, for example, the peripheral nerve bundlesincluding motor nerve bundles. The stimulation energy provided in thissystem must be large enough to compensate for propagation losses throughthe peripheral nerve while still having sufficient remaining energy toaccomplish the desired stimulation level in the dorsal root ganglion.Unlike the present invention, the stimulation energy provided byelectrode placement (b) will also apply stimulation energy to the motornerves within the peripheral nerve. Electrode placement in positions (a)and (b) above each have intervening physiological structures that aresubjected to the stimulation energy and may cause undesiredconsequences. In addition, each of the intervening physiologicalstructures will be subjected to and may attenuate or absorb thestimulation energy before the energy reaches the desired neural tissue.

Embodiments of the present invention provide stimulation energy via oneor more electrodes placed on, in or in proximity to the targeted neuraltissue. The intimate nature of the electrode placement allowssubstantially less stimulation energy to be used to achieve a comparableneurostimulation level. One reason it is believed that that lower powerlevels may be used in the inventive techniques is that the lack ofattenuation losses caused by subjecting intervening physiologicalstructures to stimulation energy. Conventional systems remain concernedabout the generation of heat and the possibility of heat induced tissuedamage because conventional stimulation systems subject interveningtissues and targeted tissues to stimulation energy. Many conventionalstimulation systems are provided with or utilize tissue temperature forcontrol or feedback. Tissue temperature is a useful parameter for theseconventional systems because they provide sufficient energy tosubstantially or measurably raise the temperature of the surroundingtissue or intervening structures. These conventional stimulation systemsraise the temperature of surrounding tissue by tens of degrees Celsiuswhile maintaining temperatures below the average temperature range thatis thermally lethal such as that used by heat lesioning procedures(i.e., below 45 C).

In contrast to systems that raise the temperature of both targeted andsurrounding tissue, it is believed that the stimulation energy levelsprovided by embodiments of the present invention are low enough that thetemperature of the targeted neural tissue does not increase a measurableamount or less than one degree Celsius. The stimulation levels providedby some embodiments of the present invention are within or below (a) themilliwatt range; (b) the millijoule range and/or (c) the microjoulerange. It is also believed that the stimulation levels provided by someembodiments of the present invention are sufficiently low that thetemperature of tissue surrounding an electrode is unaffected, increasesby less than 5 degrees C., or less than 1 degree C. Moreover, it isbelieved that the stimulation energy levels provided by otherembodiments of the present invention are low enough that the temperatureof the surrounding tissue and other physiological structures is below ameasurable amount using conventional temperature measurement techniquesor below one degree Celsius. It is to be appreciated that thestimulation energy levels provided by embodiments of the presentinvention are substantially below those conventional stimulation systemsthat measurably elevate the temperature of surrounding tissue or operateat levels approaching the level of thermal ablation and lesioning.

It is to be appreciated that embodiments of the specific stimulationtechniques of the present invention may be utilized alone to achieve thedescribed stimulation techniques or in a combined upstream or downstreamconfigurations with the described stimulation techniques and systemsdescribed in the following references (each of which is incorporatedherein in its entirety): U.S. Pat. No. 5,948,007 to Starkebaum; U.S.Pat. No. 5,417,719 to Hull; U.S. Pat. No. 6,658,302 to Kuzma; U.S. Pat.No. 6,606,521 to Paspa; and U.S. Pat. No. 5,938,690 to Law.

It may be appreciated that the neuromodulation provided to the patientis typically maintained throughout the treatment of the patient'scondition. When such treatment is for a chronic condition, theelectrodes continue to provide neuromodulation of the target anatomy,such as the dorsal root ganglion, over long periods of time and maintaina comfortable paresthesia sensation for the patient. Typically,paresthesia is provided in a distribution over the affected body regionand is maintained at a desired intensity throughout the patient's dailyactivities. As mentioned above, in some embodiments, the stimulationenergy is modified based on activity level to provide desiredparesthesia during varying activities. In other embodiments, paresthesiais maintained during varying activities to provide a continuous level ofintensity and/or distribution. This may particularly be the case when apatient changes body position between an upright position, such asstanding up, and a recombinant position, such as lying face-up orface-down. Other changes in body position include, for example, flexion,extension or rotation of a portion of the spine. With such changes inbody position, it is often desired to maintain paresthesia levels anddistribution to avoid sudden undesired surges of stimulation or otheruncomfortable sensations.

In some embodiments, at least one electrode is implanted in proximity toa target tissue, such as a dorsal root ganglion, so that the at leastone electrode maintains position in proximity to the target tissuethroughout a body position change of the patient. Such maintenance ofposition holds the electrode in relation to the target tissue so thatthe electrode does not move closer or further from the target whichwould alter the stimulation effects. For example, movement of theelectrode closer to the target would suddenly increase stimulation.Thus, sudden surges or stimulation are avoided or reduced. Maintainingposition of the at least one electrode maintains intensity ofparesthesia, distribution of paresthesia, or both.

In some embodiments, maintenance of position is achieved with the use ofan anchor. A variety of example anchors and anchoring techniques havebeen described herein, such as attaching to adjacent bony structure,soft tissue or other neighboring anatomical structures. Likewise, afixation, anchoring or bonding structure has been described, positionedproximal to an electrode anchor that absorbs some or all proximalmovement of the leads so that the electrode is less likely to be pulledfrom or dislodged from the implantation site. The goal of the anchoringand other strain absorbing features is to ensure the electrode remainsin place within or is less likely to migrate from the implanted positionbecause of electrode lead movement. It is to be appreciated thatnumerous techniques are available to aid in electrode placementincluding percutaneous placement of single/multiple hooks or anchors,vertebral anchor or posts, micro-sutures, cements, bonds and otherjoining or anchoring techniques known to those of ordinary skill in theart. In other embodiments, lack of clinically significant changes inparesthesia during movement of the patient is achieved without use of ananchor. Due to the anatomical features surrounding the dorsal rootganglion, implantation of an electrode in proximity to a dorsal rootganglion can maintain position of the electrode during body movements,such as movements of portions of the spine or changes in body position.In particular, when an electrode is positioned adjacent to a surface ofthe dorsal root ganglion, such as within a foramen, minimal cerebralspinal fluid is disposed between the electrode and the dorsal rootganglion. Typically, fluctuations in cerebral spinal fluid depth causeincreases and decreases in the distance between the electrode and thetarget tissue during body movements. However, since cerebral spinalfluid is minimized in the area of the dorsal root ganglion, suchfluctuations do not occur or are so minimal as to avoid clinicallysignificant effects in stimulation and therefore paresthesia intensityand/or distribution.

To verify the maintenance of paresthesia intensity and distributionduring body movements, various studies have been undertaken. To begin,patients having at least one electrode implanted near a dorsal rootganglion were provided stimulation energy at known levels. Referring toFIGS. 39A-39B, the patient rated the intensity of the paresthesia ateach energy level during various body positions. FIG. 39A illustrates an11 point scale 300 in which a patient rates the paresthesia intensitywhile standing up at a particular stimulation level. FIG. 39Billustrates an 11 point scale 302 in which a patient rates theparesthesia intensity while lying down at the same stimulation level. Inboth instances, a rating of “0” indicated no feeling of paresthesiawhile a rating of “10” indicated a very intense feeling of paresthesia.FIG. 40 is an example of data compiled for a given patient comparingstimulation level (current amplitude) and paresthesia intensity whilethe patient is in a particular body position. As shown, as the currentamplitude was increased, the intensity of paresthesia sensed by thepatient increased in a corresponding manner. In this example, thecoefficient of determination is 0.9812 which indicates that the data ishighly linear. Thus, it may be assumed that if a patient senses anincrease in paresthesia intensity during normal body movements, such achange in paresthesia intensity correlates directly to a change instimulation. When the stimulation parameters are held constant, such achange would be due to movement of the electrode in relation to thetarget, however slight.

FIG. 41 is a bar graph illustrating complied paresthesia intensity datafrom 22 patients. The first bar 350 indicates a paresthesia intensityvalue of 5.3 on the 11 point scale 300 when the patient is in an uprightposition and stimulation is at a given level. The second bar 352indicates a paresthesia intensity value of 5.6 on the 11 point scale 302when the patient is in a supine position and stimulation is at the samegiven level. The difference in paresthesia intensity values (5.3 vs.5.6) is not clinically significant and indicates that paresthesia ismaintained throughout these body position changes.

FIG. 42 is a line graph illustrating the maintenance of paresthesiaintensity over time. At each time point, a cohort of patients ratedparesthesia intensity on the 11 point scale 300 while in an uprightposition and paresthesia intensity on the 11 point scale 302 while in asupine position. Time points included after placement and programming ofa temporary neurostimulator (“Post-INS Programming”), at the end of thetrial period with the temporary neurostimulator (“End of TNS”), afterplacement and programming of a permanent implantable neurostimulator(“Post-INS Programming”), and at 1 week, 4 weeks, 8 weeks, 3 months, 6months, and 12 months after implantation of the permanent implantableneurostimulator. Line 350 indicates paresthesia intensity values overtime for patients while in an upright position and line 352 indicatesparesthesia intensity values over time for patients while in a supineposition. The difference in paresthesia intensity values is notclinically significant and indicates that paresthesia intensity ismaintained throughout these body position changes and is consistent overtime.

FIGS. 43A-43B are body maps illustrating paresthesia distribution. Inthis example, the patient has an electrode implanted near a dorsal rootganglion. FIG. 43A illustrates areas on the patient body P whereparesthesia is felt while the patient is in an upright position. Areasof paresthesia are indicated by shading 400. FIG. 43B illustrates areason the patient body P where paresthesia is felt while the patient is ina supine position. Areas of paresthesia are indicated by shading 402.The difference in paresthesia distribution is not clinically significantand indicates that paresthesia distribution is maintained throughoutthese body position changes.

While preferred embodiments of the present invention have been shown anddescribed herein, it will be obvious to those skilled in the art thatsuch embodiments are provided by way of example only. Numerousvariations, changes, and substitutions will now occur to those skilledin the art without departing from the invention. It should be understoodthat various alternatives to the embodiments of the invention describedherein may be employed in practicing the invention. It is intended thatthe following claims define the scope of the invention and that methodsand structures within the scope of these claims and their equivalents becovered thereby.

What is claimed is:
 1. A method of stimulating a dorsal root ganglion ofa patient, comprising: implanting at least one electrode in proximity tothe dorsal root; and activating the at least one electrode toselectively stimulate at least a portion of the dorsal root ganglion tocreate paresthesia in an area of the patient's body.